Intraarteriell administrasjon av legemidler.
Fråga: Farmasøyt etterspør litteraturliste for informasjon om intraarteriell administrasjon av legemidler.
Svar: RELIS har søkt i de fagbøker vi har tilgjengelige både i papirutgavene og elektronisk via biblioteket. Intra-arteriell administrasjon er ikke beskrevet i noe større omfang. Under gjengis et utdrag av det RELIS har funnet. RELIS har også snakket med fagperson som underviser i farmakologi ved universitetet for å få anbefalinger til litteratur. De hadde ikke kjennskap til fagbøker som tok for seg dette i noen større grad enn det vi allerede hadde funnet, men supplerte med utskrift fra enda en fagbok. Dette er lagt til som vedlegg til svaret.
Utdrag fra (1):
Intraarterial
Occasionally, a drug is injected directly into an artery to localize its effect in a particular tissue or organ, such as in the treatment of liver tumors and head/neck cancers. Diagnostic agents sometimes are administered by this route (e.g., technetium-labeled human serum albumin). Intraarterial injection requires great care and should be reserved for experts. The first-pass and cleansing effects of the lung are not available when drugs are given by this route.
Utdrag fra (2): Intentional or accidental intra-arterial drug injections by medical personnel or those taking illicit drugs can result in local vasospasm, infectious arteritis, thrombosis, pseudoaneurysm, and mycotic aneurysm. Inert particles or drug crystals can embolize to obstruct end arteries, which can lead to gangrene of digits.
Utdrag fra (3):
Intra-Arterial Injection of Drugs
Essentials of Diagnosis:
History of parenteral drug injection
Severe burning pain distal to injection site
General Considerations: Inadvertent or intentional intra-arterial injection of drugs can cause intense vasospasm followed by arterial occlusion, with distal gangrene as a possible result. This is commonly known as a "hand trip" by intravenous drug abusers. Vasospasm may occur while the drug is being given, or the reaction may be delayed. Unfortunately, many patients with delayed reactions fail to seek medical attention until ischemia is advanced.
Clinical Findings: There is a history of therapeutic or illicit drug injection by the parenteral route. Severe burning pain in distal arterial distribution is followed by intense vasospasm. If the vasospasm has been prolonged, gangrene of the fingers or entire hand may occur even though the arterial vasoconstriction subsequently resolves. Treatment & Disposition: Hospitalize the patient, and obtain vascular surgical consultation. If the needle is still in place, irrigate distally with heparinized saline. Start systemic anticoagulation with heparin. Systemic vasodilating agents may be necessary to treat the intense vasospasm. Intra-arterial injection of vasodilators (e.g., reserpine) is not usually beneficial. If sympathetic nerve block is indicated because of persistent severe peripheral ischemia, consult an anesthesiologist or vascular surgeon.
Utdrag fra (4):
Intraarterial Thrombolysis
Potential advantages of intraarterial administration include delivery of a higher concentration of an activator delivered proximally or directly into the thrombus using an appropriately placed catheter, more accurate anatomic diagnosis, the ability to observe the course of recanalization, and lower total doses of drug that might reduce intracranial hemorrhage. Problems with this approach include the need for specialized facilities and experienced personnel available at all times to perform arteriography and selective catheterization. These requirements generally result in longer times before the treatment can be delivered, and this is a critical variable in treatment success. Several small open-label trials observed a high rate of recanalization and apparent clinical benefit with intraarterial therapy using urokinase, streptokinase, or t-PA, but hemorrhagic transformation was a frequent problem. Intraarterial thrombolysis is associated with higher recanalization rates for internal carotid artery, middle cerebral artery stem, and basilar artery occlusions. Intraarterial therapy may have particular value in acute basilar artery occlusion, which has a very high mortality but clinical recovery in up to 50 percent of patients receiving intraarterial thrombolysis.
The Prolyse in Acute Cerebral Thromboembolism (PROACT) and PROACT II Trials evaluated recombinant human prourokinase by catheter-directed intraarterial administration. The PROACT Trial included 26 patients with occlusion in the territory of the middle cerebral artery who received intraarterial prourokinase and heparin and 14 patients treated with heparin alone. A significantly higher recanalization rate was observed with prourokinase treatment with no increase in intracranial hemorrhage. This led to the larger PROACT II Trial, a randomized, placebo-controlled open-label trial that included 180 patients with acute occlusion of the middle cerebral artery who were treated within 6 hours of symptom onset with either heparin alone or 9 mg of intraarterial prourokinase plus heparin. The recanalization rate was significantly higher with prourokinase (66% vs. 18%, p <0.001), and functional improvement at 90 days was also superior. Symptomatic intracranial hemorrhage occurred in 10 percent of patients treated with prourokinase and 2 percent of controls. Although promising, these results did not lead to FDA approval of intraarterial prourokinase for treatment of stroke. Cochrane Reviews of these studies are available.
A third study, the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan, evaluated 114 patients with middle cerebral artery occlusion of less than 6 hours duration who were randomized to either intraarterial urokinase treatment or placebo. The study was underpowered because of premature study closure. A favorable but not statistically significant outcome at 90 days was more likely with intraarterial urokinase compared with placebo. The proportion of patients with an excellent functional outcome defined by a modified Rankin scale at 90 days was significantly better in the intraarterial urokinase group (42% vs. 23%, p = 0.045). Intracerebral hemorrhage within 24 hours of treatment occurred in 9 percent and 2 percent, respectively (P = 0.206). This study suggested that intraarterial fibrinolysis has the potential to increase the likelihood of excellent functional outcome in appropriate clinical settings.
Overall, these studies show that treatment of acute stroke with thrombolytic therapy can lead to recanalization of the occluded artery and improvement in clinical outcomes. A critical issue is the time from symptom onset to the start of therapy. Evidence is clear that earlier treatment results in better results. The need for very early treatment is currently the single largest limitation to greater application of thrombolytic therapy for stroke. Less than 5 percent of stroke patients currently receive t-PA treatment because treatment is limited to patients presenting within 3 hours of symptom onset and because of the additional contraindication to thrombolytic therapy. The greatest impediment is the delay from the time patients experience symptoms to the time they appear in the emergency room, and focused community educational efforts must be made if this treatment is to have a greater impact. The rate of intracranial hemorrhage is high, principally as a result of hemorrhagic transformation within ischemic tissue. Despite early deaths and increased morbidity in patients affected with intracranial hemorrhage, the overall functional results among stroke patients can be improved. The results are critically dependent on both dose and choice of thrombolytic agent. Clinical studies with intravenous t-PA showed better results, whereas streptokinase was associated with an unacceptably high rate of intracranial hemorrhage. Whether this difference is a result of intrinsic properties of these agents or due to dose and treatment intensity remains controversial.
Thrombolytic therapy for stroke is an area of very active investigation with the primary goal of expanding the proportion of patients who can be successfully treated. Recent randomized studies with recombinant t-PA have provided evidence that intravenous thrombolytic therapy can be safely extended to 4.5 hours after symptom onset in selected patients.338–340 An additional goal is to reduce intracranial hemorrhage by identifying patients at greatest risk using newer imaging modalities, such as magnetic resonance imaging diffusion/perfusion mismatch to identify reversible ischemia. Studies are also evaluating newer agents including reteplase and tenecteplase. The combination of potent antiplatelet therapy using an IIb 3-integrin antagonist with a lower dose of a thrombolytic agent may improve results.363–368 Other studies are examining the combination of intravenous and intraarterial therapy and also the adjunctive use of low-intensity ultrasound to accelerate fibrinolysis.
Current recommendations limit thrombolytic therapy for stroke to patients presenting within 3 hours of symptom onset. The approved therapy is with 0.9 mg/kg (maximum 90 mg) of t-PA administered intravenously with 10 percent as an initial bolus and the remainder infused over 60 minutes. The best results are obtained in patients who meet strict eligibility requirements. Thrombolytic therapy can be considered for eligible patients within 3 to 4.5 hours of clearly defined symptom onset. Eligible patients should be treated as quickly as possible in general. Patients should be closely monitored for bleeding complications, especially intracranial hemorrhage. Facilities should be available for managing bleeding complications, and careful attention to management of blood pressure and other comorbidities is critical.
Referenser:- Buxton ILO. Chapter 1, "pharmacokinetics and pharmacodynamics: The dynamics of drug absorption, distribution, action and elimination. Brunton LL, Lazo JS, Parker KL: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11e: http://www.accessmedicine.com (13. Januar 2011).
- Chopra A, Carr D. Chapter 64. Occlusive Arterial Disease. Tintinalli JE, Stapczynski JS, Cline DM, Ma OJ, Cydulka RK, Meckler GD. Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e. http://www.accessmedicine.com (13. januar 2011).
- Fritz DA. ”Chapter 38, “Vascular emergencies” (Chapter). Stone CK, Humphries RL Current Diagnosis & Treamtent: Emergency Medicine, 6e. http://www.accessmedicine.com (13. januar 2011).
- Hajjar KA, Ruan J. Chapter 136. Fibrinolysis and Thrombolysis. Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT. Williams Hematology, 8e. http://www.accessmedicine.com (13. januar 2011).
- Chabner BA, Longo DL. Cancer Chemotherapy and biotherapy 2006; 4.th ed.: p 487.