Chemistry/Storage/Stability/Compatibility - A synthetic xanthine derivative structurally related to caffeine and theophylline, pentoxifylline occurs as a white, odorless, bitter-tasting, crystalline powder. At room temperature, approximately 77 mg are soluble in one ml of water and 63 mg in one ml of alcohol.The commercially available tablets should be stored in well-closed containers, protected from light and at 15-30°C. Pentoxifylline is also known as oxpentifylline or BL-191.
Pharmacology - The mechanisms for pentoxifylline’s actions are not fully understood. The drug increases erythrocyte flexibility probably by inhibiting erythrocyte phosphodiesterase and decreases blood viscosity by reducing plasma fibrinogen and increasing fibrinolytic activity.
Pentoxifylline is postulated to reduce negative endotoxic effects of cytokine mediators via its phosphodiesterase inhibition.
Uses/Indications - In horses, pentoxifylline has been used as adjunctive therapy for endotoxemia and in the treatment of navicular disease. At the time of writing, the drug is still under investigation to document both safety and efficacy for these purposes.
Pentoxifylline has been used in dogs to enhance healing and reduce inflammation caused by ulcerative dermatosis in Shelties and Collies and for other conditions where improved microcirculation may be of benefit.
Pentoxifylline’s major indications for humans include symptomatic treatment of peripheral vascular disease (e.g., intermittent claudication, sickle cell disease, Raynaud’s, etc.) and cerebrovascular diseases where blood flow may be impaired in the microvasculature.
Pharmacokinetics - A pharmacokinetic study done in horses showed high interpatient variability in absorption of oral dosage forms with peak levels occurring 1 - 10 hours after oral dosing. No significant difference in relative bioavailability was noted between whole and crushed extended-release tablets. The drug appears to rapidly eliminated (half life of about one hour after IV dosing). Because of the wide interpatient variability, the authors were unable to make dosing recommendations for clinical use.
In humans, pentoxifylline absorption from the gastrointestinal tract is rapid and almost complete, but a significant first-pass effect occurs. Food affects the rate, but not the extent of absorption. While the distributive characteristics have not been fully described, it is known that the drug enters maternal milk. Pentoxifylline is metabolized both in the liver and in erythrocytes and all identified metabolites appear to be active.
Contraindications/Precautions/Reproductive Safety - Pentoxifylline should be considered contraindicated in patients who have been intolerant to the drug or xanthines (e.g., theophylline, caffeine, theobromine) in the past and those with cerebral hemorrhage or retinal hemorrhage. It should be used cautiously in patients with severe hepatic or renal impairment and those at risk for hemorrhage.
Although safety in pregnant, lactating or breeding animals has not been established, studies in pregnant rats and rabbits demonstrated no overt teratogenicity. As pentoxifylline and its metabolites enter maternal milk, benefits to the mother should be weighed against the risks to offspring.
Adverse Effects/Warnings - Most commonly reported adverse effects involve the GI tract (vomiting/inappetence). There are reports of dizziness and headache occurring in a small percentage of humans receiving the drug. Other adverse effects, primarily GI, CNS and cardiovascular related have been reported in people, but are considered to occur rarely. Note: Veterinary experience is limited with pentoxifylline and animal adverse effects may differ.
Overdosage - Humans overdosed with pentoxifylline have demonstrated signs of flushing, seizures, hypotension, unconsciousness, agitation, fever, somnolence, GI distress and ECG changes. One patient who ingested 80 mg/kg recovered completely. Overdoses should be treated using the usual methods of appropriate gut emptying and supportive therapies.
Drug Interactions - Use of non-steroidal antiinflammatory agents with pentoxifylline in horses is controversial. Some sources state that when used for endotoxemia in horses, pentoxyfilline’s beneficial effects are negated by NSAIDs, but one study showed superior efficacy when flunixin and pentoxifylline were used together compared with either used alone. Ciprofloxacin (other quinolones too?) and cimetidine can increase pentoxifylline serum levels. Increased adverse effects of pentoxifylline may result. When pentoxifylline is used with warfarin or other anticoagulants, increased risk of bleeding may result. Use together with enhanced monitoring and caution. Theophylline blood levels may be increased when used concurrently with pentoxifylline.
a) To reduce the cytokine effects in endotoxemia: 8.5 mg/kg PO bid (considered to be experimental therapy) (Edens and Cargile 1997)
b) For treatment of navicular disease: 6 grams per day PO for 6 weeks (Livesay 1996)
Monitoring Parameters - Efficacy and adverse effects
Client Information - To reduce the GI effects of pentoxifylline, give with food. Clients should understand that veterinary experience with this medication is limited and that the risk versus benefit profile is not well defined.
Dosage Forms/Preparations/FDA Approval Status -
Veterinary-Approved Products: None
Pentoxifylline 400 mg extended-release tablets (pink); Trental® Tablets (Hoechst Marion Roussel), Generic; (Rx)
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