Clinical Pharmacology for Trental
Mechanism of Action
Trental (pentoxifylline) is a xanthine derivative. Itbelongs to a group of vasoactive drugs which improve peripheral blood flow andthus enhance peripheral tissue oxygenation. The mechanism by which Trentalachieves this effect has not been determined, but it is likely that thefollowing 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 plateletdeaggregation contribute to the decrease in blood viscosity.
Pharmaco*kinetics
Pentoxifylline is almost completely absorbed after oraladministration. The Trental 400 mg sustained release tablet showed an initialpeak plasma pentoxifylline concentration 2 to 3 hours post-administration. Thedrug 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 ofits parent substance. Biotransformation products are almost exclusively eliminatedby the kidneys.
Food intake before the administration of Trental delayed theabsorption but did not decrease it.
In vitro and in vivo Animal Data
Pharmacodynamics
In dogs, 10mg/kg/i.v pentoxifylline produced a short butsignificant drop in BP. 5-15 mg/kg/i.v. pentoxifylline produced a dose relatedincrease 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 bloodpressure, heart rate and respiration remained practically unchanged whereashigher doses of pentoxifylline (14-25 mg/kg/i.v.) caused a transient decreasein 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 dogsthe respiration was slightly stimulated. The blood pressure response in catsand rabbits after epinephrine was slightly inhibited by pentoxifylline. Thei.v. administration of pentoxifylline or aminophylline in doses of 3-10 mg/kgto cats resulted in a 20 and 35 % increase on dp/dt respectively.
Femoral musculature circulation in cat, measured indirectlyby heat-conduction probe, was increased by pentoxifylline (10-50 mg/kg/p.o. and1-20 mg/kg/i.v.) and papaverine (1 mg/kg/i.v) while aminophylline (1-10mg/kg/i.v) was without effect. In hepatic circulation in cat, pentoxifylline (2mg/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, (1mg/kg/i.v) produced a 4.0 mmHg increase, aminophylline 3 mg/kg/i.v. produced a1 mmHg increase in PO2 and 5 mg/kg/i.v. reduce O2 tension 1mmHg.
Reserpine pre-treatment did not influence the positivechronotropic effect of pentoxifylline in rats.
On isolated rabbit hind limb, pentoxifylline-inducedvasodilatation was comparable to acetylcholine-induced vasodilatation at equaldoses.
In isolated guinea pig heart preparation, pentoxifylline(30-600 μg) produced no significant effect on contractility or heart rateand small increase in coronary flow while aminophylline (30-808 μg)produced a biphasic effect on coronary flow, slight negative inotropism and norate alteration. The activity of pentoxifylline on coronary flow was notinfluenced by propanolol (7.5 μg). In isolated guinea pig tracheal chain,the bronchodilator activity of pentoxifylline, was significantly greater thanaminophylline. 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 sameconcentration range.
Bronchospasm induced by i.v. acetylcholine in guinea pigswas inhibited by 97%, and that induced by i.v. histamine inhibited by 100%, atpentoxifylline doses of 50 mg/kg/i.v. and 20 mg/kg/i.v. respectively.
On rabbit aorta strip preparation both pentoxifylline andaminophylline inhibited the NE-induced contraction.
The histamine-induced increase of capillary permeability inrats was not influenced by 10 or 25 mg/kg pentoxifylline i.p.
Pentoxifylline given orally (25-100 mg/kg) to rats had noinfluence on blood sugar while in rabbits given i.v. (10-50 mg/kg) the higherdose pentoxifylline increased blood sugar from 100 to 187 mg% at 1 hourpost-dosing.
In comparison to aminophylline, the central stimulatoryeffect of pentoxifylline in rats was significantly milder. Pentoxifylline (40and 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 inducedby 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 wasadded to blood from human volunteers, and in vivo studies in whichpentoxifylline was given orally or intravenously to patients with peripheralvascular disease indicate that pentoxifylline can improve impaired erythrocyte flexibility. The possible mechanism involved in this effect are most likelyrelated to intracellular adenosine triphosphate (ATP) inasmuch as ATP depletedcells have reduced flexibility and vice versa. Pentoxifylline raiseserythrocytes intracellular ATP concentrations. In another in vitro study usingrat erythrocytes, pentoxifylline has been shown to decrease intracellular Ca++ concentrationsand increase phosphorylation of the proteins in the erythrocytes membrane byfacilitating Mg++ dependent phosphoprotein phosphatase and transglutaminase activity.This results in an increased membrane phosphoprotein concentration, which isbelieved to increase red blood cell flexibility.
In an in vivo rat study designed to test plateletdeaggregation properties of drugs, pentoxifylline at doses of 3,6 and 12mg/kg/i.v. reduced platelet aggregation to “sticky” cancer cells (Walker 256carcinosarcoma) and inhibited their attachment to endothelium. Monkeys given pentoxifylline6, 12, 18 and 24 mg/kg/i.v. exhibited dose related reduction in plateletaggregation index. In human pentoxifylline inhibits ADP-stimulated plateletaggregation as measured by the Born method.
Epinephrine-induced lipolysis (rat epididymal adipose tissue) was increased by pentoxifylline and aminophylline at 10-3 and10-4 M in vitro. In vivo, epinephrine-induced glycerine production (sametissue) was significantly inhibited by both compounds (10 mg/kg/i.v.) and FFAwas decreased.
Pharmaco*kinetics
Beagle dogs were given 3.0 mg/kg/p.o pentoxifylline-14C andradioactivity measured in plasma and body tissues. Mean maximal blood levels(2.1 μg/mL) were reached 1 hour post-dosing. Plasma concentration/timecurve displayed a biphasic elimination profile with t1/2 0.8 hours and 30hours. Over 80% of the radioactivity was found in urine within 24 hours. Atmaximal blood levels time, highest concentration was found in gallbladder (110.0 μg/g), kidney, liver and bladder (4.8 μg/g): lowestconcentrations were found in brain (0.40 μg/g), fat, heart and gonads (1.3μg/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 orallydosed animals, increased or irregular respiration, tonic-clonic convulsions and paresis.
Rabbits survived 50 mg i.v; signs and symptoms of toxicitywere 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 dosesof 0, 12.5, 25, 50 or 100 mg/kg of pentoxifylline. One mouse of the highestdosage group died after 6 days. Death was preceded by dyspnea and clonicconvulsions. The other animals of this group showed a decrease in spontaneousactivity and had their eyes closed.
Mouse, p.o., 78 weeks:
Four groups of 20 males and females were givenpentoxifylline in diet at 0, 50, 150 or 450 mg/kg/day. Five animals per sex pergroup were killed after 26 weeks and another 5 at 52 weeks. After 78 weeks theremaining 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 thancontrols. High dose females showed a greater frequency of bronchiectasis, fattydegeneration 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 anduterine tumours, and angiosarcoma of the liver was observed in 1 animal of eachsex in the high dose group.
Rat, i.v., 14 days:
Groups of 10 females were given pentoxifylline at dailydoses of 0, 12.5, 25, 50 or 100 mg/kg. Four of the 10 rats given 100 mg/kgshowed depressed spontaneous activity, staggering gait, closed eyelids,salivation and clonic and tonic convulsions and died. There were pulmonary hemorrhagesin these 4 rats.
Rat, i.v, 30 days:
Groups of 10 males and 10 females were given pentoxifyllinein 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 aslight increase in the mean blood glucose level in the 25 and 50 mg/kg femalegroups. Perilobular hyaline droplet degeneration of the liver occurred in allgroups, but appeared to be more severe in the male rats of the two highestdosage 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 pentoxifyllinein their diet 0, 50, 150 or 450 mg/kg/day. Five animals per sex per group werekilled at 52 weeks and another 5 at 78 weeks. After 78 weeks the remaininganimals were observed for 26 weeks without additional exposure topentoxifylline. In the middle-dose group the body weight gain was significantlydecreased; at the end of the 6 months follow-up period the body weight werenormal. In the high-dosage group the body weight gain was decreased. At the endof the 6 months follow-up period the female weight had returned to normal butthe males had not. The mortality rate was significantly increased for the malesin the high-dose group. The cause of death was similar in treated and untreatedanimals, but in the treated animals there was an increase in congestive streaksof the liver, cadiosclerosis and scars in the heart, dilatation of the uterus,and thyroid atrophy (females only). There were more interstitial cell tumoursof the testicl*s in the high dosage group but the difference was notsignificant. 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 givenpentoxifylline in doses of 0, 10, 25 and 63 mg/kg 5days/week for 6 weeks. Therewas licking of the lips, vomiting, incoordination, uneasiness and dose-relatedheart rate increase following the injection. Some tubular renal degenerationoccurred at 25 and 63 mg/kg. There was also congestion of liver at these dosesand congestion of spleen at the highest dose.
Dog, p.o., 1 year:
Groups of 3 male and 3 female Beagles were givenpentoxifylline in doses of 0, 32, 100, 320 or 400 mg/kg/day. There wasincoordination, salivation and altered temperament following drug administration.Deaths occurred at doses of 320 and 400 mg/kg due to extensive or focal pulmonaryoedema and hemorrhages, and marked congestion in mucosa of the intestinaltract. Acetone was detected in urine at 2 weeks to 26 weeks in some dogs of the3 highest dose groups. At 52 weeks acetone was no longer detected. Giant cellformation in the testicl*s was observed in 2 dogs, which died in the 320 mg/kggroup. Granuloma in the lymph nodes occurred in 1 dog in the control group, and2 in the 320 mg/kg group.
Reproduction and Teratology
Mouse, i.v.:
Mice were given 0, 12.5, 25 or 50 mg/kg pentoxifylline fromday 15 of gestation through day 21 of lactation. Between days 21 and 23 all theanimals were killed. Some of the F1 offspring were reared and mated. Thefemales and F2 offspring were raised to weaning, and then killed. All other F1 offspringwere killed at 10 weeks. There was no significant effect on pregnancy and on thefetal development.
Rat, p.o.:
Groups of 10 males and 20 females were given 0, 57, 170 or570 mg/kg/day pentoxifylline for 10 weeks before mating and then continuouslythrough gestation and lactation. Fifty percent of the females were killed onthe 13th day of gestation and the remaining animals were allowed to raise theiryoung to weaning.
The number of resorptions, particularly early resorption,was greater in the high dose group. The number of young reared to weaning waslower for the high dose group.
Rat, p.o. and i.v.:
Groups of 20 females were given pentoxifylline 0, 57, 100 or570 mg/kg orally or 0.8, 3.2 or 12.5 mg/kg i.v. from the 6th or 7th day to the16th day of gestation. Two control groups were used in the i.v. study. Onegroup was given a volume of physiological NaCl similar to the treatment groupsand the other group was not treated at all. On the 20th day of pregnancy thefetuses were removed by Caesarean section. There was a significant reduction inthe number of fetuses in the highest oral dosage group and the number of resorptionsites was increased. There were no fetal abnormalities. The highest i.v. dosecaused a slight reduction in number of fetuses and increase in resorption.
Rat, p.o.:
Groups of 20-24 pregnant animals were given pentoxifylline0, 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 drugeffects.
Rabbit, i.v. and p.o.:
Groups of 10 pregnant females were given pentoxifylline at0, 26.5, 80 or 265 mg/kg/day orally or 1, 3.2, 0r 10 mg/kg/i.v./day. There wereno drug effects.
REFERENCES
1. Angelkort B: Influence of pentoxifylline (Trental 400) on microcirculation, poststenotic blood pressure and walking capacity in patientswith chronic occlusive arterial disease. IRCS Med Sci 1977; 5: 370.
2. Angelkort B: Platelet function, plasma coagulation andfibrinolysis 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 undertreatment 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. Pharmacotherapy1977; 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 flowproperties 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 Yorkand London 1976; 165-166.
9. Gastpar H, Ambrus JL, Ambrus CM, et al: Study of plateletaggregation in-vivo III. Effect of pentoxifylline. J Med 1977; 8: 191.
10. Heidrich H, Schlichting K, Ott M: Change in bloodviscosity 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 indiabetics with peripheral vascular disorders. Pharmacotherapy 1976; 1: 172-179.
14. Stefanovich V: The biochemical mechanism of action ofpentoxifylline. Pharmacotherapy 1978; 2(1): 5-16.
15. Stefanovich V: Effect of pentoxifylline on energy richphosphates 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 PathPharmacol 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 arterialdisease. Pharmacotherapy 1978; 2(1): 51-57.
19. Weed RI, LaCelle PL, Merrill EW: Metabolic dependence ofred 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.
