Trental

CLINICAL PHARMACOLOGY

Mechanism of Action

Trental (pentoxifylline) is a xanthine derivative. It belongs to a group of vasoactive drugs which improve peripheral blood flow and thus enhance peripheral tissue oxygenation. The mechanism by which Trental achieves this effect has not been determined, but it is likely that the following factors are involved:

  • Trental, as with other xanthine derivatives, relaxes certain smooth muscles including those of the peripheral vessels, thus causing vasodilatation or preventing spasm. This action, however, may have a limited role in patients with chronic obstructive arterial disease when peripheral vessels are already maximally dilated.
  • Trental improves flexibility of red blood cells. This increase in the flexibility of red blood cells probably contributes to the improvement of the ability of blood to flow through peripheral vessels (haemorheologic action). This property was seen during in vitro and in vivo experiments with Trental but the correlation between it and the clinical improvement of patients with peripheral vascular diseases has not been determined.
  • Trental promotes platelet deaggregation.

Improvement of red blood cell flexibility and platelet deaggregation contribute to the decrease in blood viscosity.

Pharmacokinetics

Pentoxifylline is almost completely absorbed after oral administration. The Trental 400 mg sustained release tablet showed an initial peak plasma pentoxifylline concentration 2 to 3 hours post-administration. The drug is extensively metabolized. The active main metabolite 1-(5- hydroxyhexyl)-3,7-dimethyl-xanthine (metabolite I) is measurable in twice the concentration in plasma of that of its parent substance. Biotransformation products are almost exclusively eliminated by the kidneys.

Food intake before the administration of Trental delayed the absorption but did not decrease it.

In vitro and in vivo Animal Data

Pharmacodynamics

In dogs, 10mg/kg/i.v pentoxifylline produced a short but significant drop in BP. 5-15 mg/kg/i.v. pentoxifylline produced a dose related increase in heart rate and decrease in peripheral resistance for 30-60 minutes. In dogs, cats, and rats, after 1-3 mg/kg pentoxifylline i.v. the blood pressure, heart rate and respiration remained practically unchanged whereas higher doses of pentoxifylline (14-25 mg/kg/i.v.) caused a transient decrease in blood pressure and an increase in heart rate. In rabbits pentoxifylline (2-10 mg/kg/i.v.) produced a dose related fall in BP. In rabbits, cats and dogs the respiration was slightly stimulated. The blood pressure response in cats and rabbits after epinephrine was slightly inhibited by pentoxifylline. The i.v. administration of pentoxifylline or aminophylline in doses of 3-10 mg/kg to cats resulted in a 20 and 35 % increase on dp/dt respectively.

Femoral musculature circulation in cat, measured indirectly by heat-conduction probe, was increased by pentoxifylline (10-50 mg/kg/p.o. and 1-20 mg/kg/i.v.) and papaverine (1 mg/kg/i.v) while aminophylline (1-10 mg/kg/i.v) was without effect. In hepatic circulation in cat, pentoxifylline (2 mg/kg/i.v) was as effective as papaverine (1 mg/kg/i.v.) in increasing blood flow.

In carotid artery blood of anaesthetized cat, pentoxifylline (5 mg/kg/i.v.) produced a 5.8 mmHg increase in PO2 whereas papaverine, (1 mg/kg/i.v) produced a 4.0 mmHg increase, aminophylline 3 mg/kg/i.v. produced a 1 mmHg increase in PO2 and 5 mg/kg/i.v. reduce O2 tension 1mmHg.

Reserpine pre-treatment did not influence the positive chronotropic effect of pentoxifylline in rats.

On isolated rabbit hind limb, pentoxifylline-induced vasodilatation was comparable to acetylcholine-induced vasodilatation at equal doses.

In isolated guinea pig heart preparation, pentoxifylline (30-600 μg) produced no significant effect on contractility or heart rate and small increase in coronary flow while aminophylline (30-808 μg) produced a biphasic effect on coronary flow, slight negative inotropism and no rate alteration. The activity of pentoxifylline on coronary flow was not influenced by propanolol (7.5 μg). In isolated guinea pig tracheal chain, the bronchodilator activity of pentoxifylline, was significantly greater than aminophylline. The presence of propanolol 10-6 g/mL did not affect results.

Contractions induced in isolated guinea pig seminal vesicle by epinephrine were reduced by pentoxifylline and by aminophylline in the same concentration range.

Bronchospasm induced by i.v. acetylcholine in guinea pigs was inhibited by 97%, and that induced by i.v. histamine inhibited by 100%, at pentoxifylline doses of 50 mg/kg/i.v. and 20 mg/kg/i.v. respectively.

On rabbit aorta strip preparation both pentoxifylline and aminophylline inhibited the NE-induced contraction.

The histamine-induced increase of capillary permeability in rats was not influenced by 10 or 25 mg/kg pentoxifylline i.p.

Pentoxifylline given orally (25-100 mg/kg) to rats had no influence on blood sugar while in rabbits given i.v. (10-50 mg/kg) the higher dose pentoxifylline increased blood sugar from 100 to 187 mg% at 1 hour post-dosing.

In comparison to aminophylline, the central stimulatory effect of pentoxifylline in rats was significantly milder. Pentoxifylline (40 and 200 mg/kg/p.o.) did not prevent convulsions induced by nicotine in mice. Pentoxifylline does not influence significantly the motility of mice and rats, food consumption of rats, sleeping time after hexobarbital in rats and mice, ptosis, sedation and hypothermia of mice caused by reserpine, catalepsy in rats induced by perphenazine of fighting behaviour in mice. It has no anticonvulsive, anti-inflammatory and local anaesthetic activity and exhibits only a slight analgesic, cholorectic, diuretic and antitussive effect.

The results of in vitro studies in which pentoxifylline was added to blood from human volunteers, and in vivo studies in which pentoxifylline was given orally or intravenously to patients with peripheral vascular disease indicate that pentoxifylline can improve impaired erythrocyte flexibility. The possible mechanism involved in this effect are most likely related to intracellular adenosine triphosphate (ATP) inasmuch as ATP depleted cells have reduced flexibility and vice versa. Pentoxifylline raises erythrocytes intracellular ATP concentrations. In another in vitro study using rat erythrocytes, pentoxifylline has been shown to decrease intracellular Ca++ concentrations and increase phosphorylation of the proteins in the erythrocytes membrane by facilitating Mg++ dependent phosphoprotein phosphatase and transglutaminase activity. This results in an increased membrane phosphoprotein concentration, which is believed to increase red blood cell flexibility.

In an in vivo rat study designed to test platelet deaggregation properties of drugs, pentoxifylline at doses of 3,6 and 12 mg/kg/i.v. reduced platelet aggregation to “sticky” cancer cells (Walker 256 carcinosarcoma) and inhibited their attachment to endothelium. Monkeys given pentoxifylline 6, 12, 18 and 24 mg/kg/i.v. exhibited dose related reduction in platelet aggregation index. In human pentoxifylline inhibits ADP-stimulated platelet aggregation as measured by the Born method.

Epinephrine-induced lipolysis (rat epididymal adipose tissue) was increased by pentoxifylline and aminophylline at 10-3 and 10-4 M in vitro. In vivo, epinephrine-induced glycerine production (same tissue) was significantly inhibited by both compounds (10 mg/kg/i.v.) and FFA was decreased.

Pharmacokinetics

Beagle dogs were given 3.0 mg/kg/p.o pentoxifylline-14C and radioactivity measured in plasma and body tissues. Mean maximal blood levels (2.1 μg/mL) were reached 1 hour post-dosing. Plasma concentration/time curve displayed a biphasic elimination profile with t1/2 0.8 hours and 30 hours. Over 80% of the radioactivity was found in urine within 24 hours. At maximal blood levels time, highest concentration was found in gallbladder (110.0 μg/g), kidney, liver and bladder (4.8 μg/g): lowest concentrations were found in brain (0.40 μg/g), fat, heart and gonads (1.3 μg/g).

Toxicology

Acute Toxicity

ACUTE TOXICITY (LD50) OF PENTOXIFYLLINE

SPECIES ROUTE LD50(MG/KG)
Mouse p.o 1385
i.v. 197
i.p 239
Rat (SD) p.o 1772
i.v. 231

Toxicity was characterized by hypersalivation in orally dosed animals, increased or irregular respiration, tonic-clonic convulsions and paresis.

Rabbits survived 50 mg i.v; signs and symptoms of toxicity were similar to those seen in rats. Dogs survived 160 mg i.v and 320 mg p.o. They showed aggression and ataxia after oral dosing and aggression, fear, vomiting, diarrhea after i.v dosing.

Subacute and Chronic Toxicity

Mouse i.v., 14 days:

Groups of 8 female 12 week old mice were given daily doses of 0, 12.5, 25, 50 or 100 mg/kg of pentoxifylline. One mouse of the highest dosage group died after 6 days. Death was preceded by dyspnea and clonic convulsions. The other animals of this group showed a decrease in spontaneous activity and had their eyes closed.

Mouse, p.o., 78 weeks:

Four groups of 20 males and females were given pentoxifylline in diet at 0, 50, 150 or 450 mg/kg/day. Five animals per sex per group were killed after 26 weeks and another 5 at 52 weeks. After 78 weeks the remaining animals were observed for 13 weeks, without exposure to the compound. High dose males showed a greater frequency of bronchiectasis, renal cysts, testicular atrophy, urinary bladder dilatation and bone marrow hyperplasia than controls. High dose females showed a greater frequency of bronchiectasis, fatty degeneration of the liver, fatty degeneration/amyloidosis in the kidneys, splenic hyperplasia, hyperplasia and fibrosis of bone marrow and osteoporosis than controls.

There was an increased incidence of benign ovarian and uterine tumours, and angiosarcoma of the liver was observed in 1 animal of each sex in the high dose group.

Rat, i.v., 14 days:

Groups of 10 females were given pentoxifylline at daily doses of 0, 12.5, 25, 50 or 100 mg/kg. Four of the 10 rats given 100 mg/kg showed depressed spontaneous activity, staggering gait, closed eyelids, salivation and clonic and tonic convulsions and died. There were pulmonary hemorrhages in these 4 rats.

Rat, i.v, 30 days:

Groups of 10 males and 10 females were given pentoxifylline in doses of 0, 10, 25 or 50 mg/kg/day. There was a slight decrease in cholesterol and esterified cholesterol in the 25 and 50 mg/kg male groups and a slight increase in the mean blood glucose level in the 25 and 50 mg/kg female groups. Perilobular hyaline droplet degeneration of the liver occurred in all groups, but appeared to be more severe in the male rats of the two highest dosage groups. Females on the top dose displayed increased incidence of renal tubule calcification.

Rat, p.o., 78 weeks:

Groups of 70 males and 70 females were given pentoxifylline in their diet 0, 50, 150 or 450 mg/kg/day. Five animals per sex per group were killed at 52 weeks and another 5 at 78 weeks. After 78 weeks the remaining animals were observed for 26 weeks without additional exposure to pentoxifylline. In the middle-dose group the body weight gain was significantly decreased; at the end of the 6 months follow-up period the body weight were normal. In the high-dosage group the body weight gain was decreased. At the end of the 6 months follow-up period the female weight had returned to normal but the males had not. The mortality rate was significantly increased for the males in the high-dose group. The cause of death was similar in treated and untreated animals, but in the treated animals there was an increase in congestive streaks of the liver, cadiosclerosis and scars in the heart, dilatation of the uterus, and thyroid atrophy (females only). There were more interstitial cell tumours of the testicles in the high dosage group but the difference was not significant. There was a significant increase in fibroadenomas of the mammary gland (females) in the high dose group.

Dog, i.v., 30 days:

Groups of 3 male and 3 female Beagles were given pentoxifylline in doses of 0, 10, 25 and 63 mg/kg 5days/week for 6 weeks. There was licking of the lips, vomiting, incoordination, uneasiness and dose-related heart rate increase following the injection. Some tubular renal degeneration occurred at 25 and 63 mg/kg. There was also congestion of liver at these doses and congestion of spleen at the highest dose.

Dog, p.o., 1 year:

Groups of 3 male and 3 female Beagles were given pentoxifylline in doses of 0, 32, 100, 320 or 400 mg/kg/day. There was incoordination, salivation and altered temperament following drug administration. Deaths occurred at doses of 320 and 400 mg/kg due to extensive or focal pulmonary oedema and hemorrhages, and marked congestion in mucosa of the intestinal tract. Acetone was detected in urine at 2 weeks to 26 weeks in some dogs of the 3 highest dose groups. At 52 weeks acetone was no longer detected. Giant cell formation in the testicles was observed in 2 dogs, which died in the 320 mg/kg group. Granuloma in the lymph nodes occurred in 1 dog in the control group, and 2 in the 320 mg/kg group.

Reproduction and Teratology

Mouse, i.v.:

Mice were given 0, 12.5, 25 or 50 mg/kg pentoxifylline from day 15 of gestation through day 21 of lactation. Between days 21 and 23 all the animals were killed. Some of the F1 offspring were reared and mated. The females and F2 offspring were raised to weaning, and then killed. All other F1 offspring were killed at 10 weeks. There was no significant effect on pregnancy and on the fetal development.

Rat, p.o.:

Groups of 10 males and 20 females were given 0, 57, 170 or 570 mg/kg/day pentoxifylline for 10 weeks before mating and then continuously through gestation and lactation. Fifty percent of the females were killed on the 13th day of gestation and the remaining animals were allowed to raise their young to weaning.

The number of resorptions, particularly early resorption, was greater in the high dose group. The number of young reared to weaning was lower for the high dose group.

Rat, p.o. and i.v.:

Groups of 20 females were given pentoxifylline 0, 57, 100 or 570 mg/kg orally or 0.8, 3.2 or 12.5 mg/kg i.v. from the 6th or 7th day to the 16th day of gestation. Two control groups were used in the i.v. study. One group was given a volume of physiological NaCl similar to the treatment groups and the other group was not treated at all. On the 20th day of pregnancy the fetuses were removed by Caesarean section. There was a significant reduction in the number of fetuses in the highest oral dosage group and the number of resorption sites was increased. There were no fetal abnormalities. The highest i.v. dose caused a slight reduction in number of fetuses and increase in resorption.

Rat, p.o.:

Groups of 20-24 pregnant animals were given pentoxifylline 0, 57, 170 or 570mg/kg by stomach tube from day 17 of gestation to day 21 postpartum. Between days 21 and 23 all animals were killed. There were no drug effects.

Rabbit, i.v. and p.o.:

Groups of 10 pregnant females were given pentoxifylline at 0, 26.5, 80 or 265 mg/kg/day orally or 1, 3.2, 0r 10 mg/kg/i.v./day. There were no drug effects.

REFERENCES

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

2. Angelkort B: Platelet function, plasma coagulation and fibrinolysis in chronic arterial occlusive disease. Med Welt 1979; 30: 1239.

3. Angelkort B: Influence of pentoxifylline on erythrocyte deformability in peripheral occlusive arterial disease. Curr Med Res Opin 1979; 6: 255.

4. Bauman JC: Doppler ultrasonic blood pressure measurements in limbs with occlusive arterial disease in normal lower extremities under treatment with pentoxifylline. IRCS Med Sci 1976; 4: 93.

5. Bollinger A, Frei C: Double-blind study of pentoxifylline against placebo in patients with intermittent claudication. Pharmacotherapy 1977; 2: 557- 562.

6. Dettori AG, et al.: Acenocoumarol and pentoxifylline in intermittent claudication. A controlled clinical study. Angiology 1989; 40(4), Part I: 237-248.

7. Ehrly AM: The effect of pentoxifylline on the flow properties of human blood. Curr Med Res Opin 1978; 5: 608-613.

8. Ehrly AM, Saeger-Lorenz K: Increased capillary flow rate of erythrocyte in hyperosmolar human blood by the addition of pentoxifylline. In Microcirculation, Vol. 1. Eds. Graysorl J, Zingg W. Plenum Press, New York and London 1976; 165-166.

9. Gastpar H, Ambrus JL, Ambrus CM, et al: Study of platelet aggregation in-vivo III. Effect of pentoxifylline. J Med 1977; 8: 191.

10. Heidrich H, Schlichting K, Ott M: Change in blood viscosity due to pentoxifylline. IRCS Med Sci 1976; 4: 368.

11. Porter JM, Cutler BS, Lee BY, et al: Pentoxifylline in the treatment of intermittent claudication: a double-blind trial with objective assess ment. Am Heart J 1982; 104(1): 66-72.

12. Schindler H: The clinical use of pentoxifylline. Pharmacotherapy 1977; 2(1): 66-73.

13. Schubotz R: Double-blind trial of pentoxifylline in diabetics with peripheral vascular disorders. Pharmacotherapy 1976; 1: 172-179.

14. Stefanovich V: The biochemical mechanism of action of pentoxifylline. Pharmacotherapy 1978; 2(1): 5-16.

15. Stefanovich V: Effect of pentoxifylline on energy rich phosphates in rat's erythrocytes. Res Comm Chem Path Pharmacol 1975; 10: 747.

16. Stefanovich V: Concerning specificity of the influence of pentoxifylline on various cyclic AmP phosphodiesterases. Res Comm Chem Path Pharmacol 1974; 8: 673.

17. United States Pharmacopeial Convention, Inc. USP DI, 13th edition 1993; 1: 2203.

18. Usvatova LJ, Koschkin VM, Musin II, et al: The haemodynamic and metabolic effects of pentoxifylline and papaverine in peripheral arterial disease. Pharmacotherapy 1978; 2(1): 51-57.

19. Weed RI, LaCelle PL, Merrill EW: Metabolic dependence of red cell deformability. J Clin Invest 1969; 48: 795.

20. Weithmann KV: Pentoxifylline, its influence on interaction between blood vessel wall and platelets. IRCS Med Sci 1980; 8: 293.

Last reviewed on RxList: 7/16/2012
This monograph has been modified to include the generic and brand name in many instances.

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