Efficacy of controlled-release papaverine pellets in preventing symptomatic cerebral vasospasm

Restricted access

Object. Vasospasm as a complication of subarachnoid hemorrhage is a major concern in clinical practice. The systemic drugs in current use are of limited value. Topical, intrathecal, or intraarterial papaverine administered during surgical or angiographic procedures is a potent vasodilating drug; however, hypotension limits its systemic application. Local application of papaverine in a biodegradable controlled- or sustained-release matrix is proposed for vasospasm prophylaxis to be used in patients scheduled for aneurysm surgery.

Methods. Controlled-release papaverine (PapaCR) drug pellets were prepared using the biodegradable aliphatic polyester poly(DL-lactide-co-glycolide) as the carrier matrix. In vitro tests were performed to determine drug kinetics. One hundred seventeen patients, 73 assigned to the control group and 44 assigned to the PapaCR-treated group, participated in this study. Patients who were deemed to be at high risk for the development of vasospasm were selected to participate in the study. During aneurysm surgery, drug pellets were placed in cisterns over arterial segments. In two patients, cerebrospinal fluid was sampled every 6 hours for the first 5 days through a lumbar catheter that had been inserted at the beginning of aneurysm surgery. The incidence of clinical vasospasm and Glasgow Outcome Scale scores in the patients were evaluated statistically.

The results of in vitro studies showed that effective local concentrations of papaverine could be maintained for more than 10 days. The first-degree drug-release profile was demonstrated using this design. In clinical studies no adverse effects due to the drug were seen. The PapaCR effectively prevented development of clinical vasospasm, and outcome scores were significantly better in patients in the treated group.

Conclusions. Local application of controlled- or sustained-release papaverine can be safely used in preventing vasospasm.

Article Information

Address reprint requests to: Tayfun Dalbasti, M.D., Department of Neurosurgery, University of Ege, School of Medicine, Bornova 35100, Izmir, Turkey. email: dalbasti@med.ege.edu.tr.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Drawing showing the experimental setup for the in vitro dissolution tests. aCSF = artificial CSF.

  • View in gallery

    Plots showing the in vitro release kinetics of PapaCR. A: Concentration of papaverine measured from samples taken every 6 hours. The thick line indicates average measurements from dissolutions of five pellets produced in one batch. There is a burst release of the drug at the beginning, followed by an approximately linear decay that lasts until the end of the 2nd week. The upper and lower thin lines reflect the maximum and minimum values for the same batch. B: Cumulative release of papaverine in which every fifth point is shown to clarify the plot. A second-order curve fit is plotted as the dotted line connecting these data points.

  • View in gallery

    Graph demonstrating drug concentrations in two patients, which were measured from samples taken from the lumbar drainage catheter over a 5-day period.

  • View in gallery

    Quantile—quantile plots of timing of operation (date post-SAH; A) and patient age (B) distribution of patients. Linearity of the plots confirms that control and treatment groups shared similar distribution.

  • View in gallery

    Box plots demonstrating Fisher grades (A), timing of operation (B), and patient age (C) distributions of patients in the control and treatment groups.

  • View in gallery

    Bar graphs depicting the distribution of patients according to aneurysm location. Both control (dark bars) and treatment (light bars) groups have the same distribution statistically (p < 0.05). ach = anterior choroidal artery; acom = anterior communicating artery; a1 and a2 = A1 and A2 segments of anterior cerebral artery, respectively; ica = internal carotid artery; mca = middle cerebral artery bifurcation; oph = ophthalmic artery; pcom = posterior communicating artery; p2 = P2 segment of posterior cerebral artery.

  • View in gallery

    Bar graphs demonstrating the numbers of patients classified by aneurysm locations who experienced vasospasm in control (upper) and treatment (lower) groups. Dark bars = no vasospasm; light bars = vasospasm.

  • View in gallery

    Histograms displaying the relationship between presence of vasospasm and Fisher grades in control (A) and treatment (B) groups. Spasm + = vasospasm; spasm − = no vasospasm.

  • View in gallery

    Histograms demonstrating patient distribution according to the GOS scores. In the treatment group (B), all patients fully recovered (GOS score of 5), except two with minor deficits (GOS score of 4).

References

  • 1.

    Athanasiou KANiederauer GGAgrawal CM: Sterilization, toxicity, biocompatibility and clinical applications of polylactic acid/polyglycolic acid copolymers. Biomaterials 17:931021996Athanasiou KA Niederauer GG Agrawal CM: Sterilization toxicity biocompatibility and clinical applications of polylactic acid/polyglycolic acid copolymers. Biomaterials 17:93–102 1996

  • 2.

    Barrows TH: Degradable implant materials: a review of synthetic absorbable polymers and their applications. Clin Materials 1:2332571986Barrows TH: Degradable implant materials: a review of synthetic absorbable polymers and their applications. Clin Materials 1:233–257 1986

  • 3.

    Bejjani GKBank WOOlan WJet al: The efficacy and safety of angioplasty for cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery 42:9799871998Bejjani GK Bank WO Olan WJ et al: The efficacy and safety of angioplasty for cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery 42:979–987 1998

  • 4.

    Feigin VLRinkel GJEAlgra Aet al: Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review. Neurology 50:8768831998Feigin VL Rinkel GJE Algra A et al: Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review. Neurology 50:876–883 1998

  • 5.

    Fisher CMKistler JPDavis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6:191980Fisher CM Kistler JP Davis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6:1–9 1980

  • 6.

    Heffez DSLeong KW: Sustained release of papaverine for the treatment of cerebral vasospasm: in vitro evaluation of release kinetics and biological activity. J Neurosurg 77:7837871992Heffez DS Leong KW: Sustained release of papaverine for the treatment of cerebral vasospasm: in vitro evaluation of release kinetics and biological activity. J Neurosurg 77:783–787 1992

  • 7.

    Jennett BBond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1:4804841975Jennett B Bond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1:480–484 1975

  • 8.

    Kaku YYonekawa YTsukahara Tet al: Superselective intra-arterial infusion of papaverine for the treatment of cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg 77:8428471992Kaku Y Yonekawa Y Tsukahara T et al: Superselective intra-arterial infusion of papaverine for the treatment of cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg 77:842–847 1992

  • 9.

    Kassell NFHelm GSimmons Net al: Treatment of cerebral vasospasm with intra-arterial papaverine. J Neurosurg 77:8488521992Kassell NF Helm G Simmons N et al: Treatment of cerebral vasospasm with intra-arterial papaverine. J Neurosurg 77:848–852 1992

  • 10.

    Kassell NFSasaki TColohan ARTet al: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 16:5625721985Kassell NF Sasaki T Colohan ART et al: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 16:562–572 1985

  • 11.

    Kassell NFTorner JCJane JAet al: The International Cooperative Study on the Timing of Aneurysm Surgery. Part 2: Surgical results. J Neurosurg 73:37471990Kassell NF Torner JC Jane JA et al: The International Cooperative Study on the Timing of Aneurysm Surgery. Part 2: Surgical results. J Neurosurg 73:37–47 1990

  • 12.

    Kuwayama AZervas NTShintani Aet al: Papaverine hydrochloride and experimental hemorrhagic cerebral arterial spasm. Stroke 3:27331972Kuwayama A Zervas NT Shintani A et al: Papaverine hydrochloride and experimental hemorrhagic cerebral arterial spasm. Stroke 3:27–33 1972

  • 13.

    Nakagomi TKassell NFHongo Ket al: Pharmacological reversibility of experimental cerebral vasospasm. Neurosurgery 27:5825861990Nakagomi T Kassell NF Hongo K et al: Pharmacological reversibility of experimental cerebral vasospasm. Neurosurgery 27:582–586 1990

  • 14.

    Oda YOkamura TMorimoto Met al: [Topical application of papaverine for cerebral vasospasm using prolonged release pellet—experimental studies.] No Shinkei Geka 11:102710341983 (Jpn)Oda Y Okamura T Morimoto M et al: [Topical application of papaverine for cerebral vasospasm using prolonged release pellet—experimental studies.] No Shinkei Geka 11:1027–1034 1983 (Jpn)

  • 15.

    Ogata MMarshall BMLougheed WM: Observations on the effects of intrathecal papaverine in experimental vasospasm. J Neurosurg 38:20251973Ogata M Marshall BM Lougheed WM: Observations on the effects of intrathecal papaverine in experimental vasospasm. J Neurosurg 38:20–25 1973

  • 16.

    Segawa HSaito IOkada Tet al: Efficacy of intracisternal papaverine on symptomatic vasospasm. Neurol Surg 14:8478541986Segawa H Saito I Okada T et al: Efficacy of intracisternal papaverine on symptomatic vasospasm. Neurol Surg 14:847–854 1986

  • 17.

    Shibuya MSuzuki YEnomoto Het al: Effects of prophylactic intrathecal administrations of nicardipine on vasospasm in patients with severe aneurysmal subarachnoid haemorrhage. Acta Neurochir 131:19251994Shibuya M Suzuki Y Enomoto H et al: Effects of prophylactic intrathecal administrations of nicardipine on vasospasm in patients with severe aneurysmal subarachnoid haemorrhage. Acta Neurochir 131:19–25 1994

  • 18.

    Shiokawa KKasuya HMiyajima Met al: Prophylactic effect of papaverine prolonged-release pellets on cerebral vasospasm in dogs. Neurosurgery 42:1091161998Shiokawa K Kasuya H Miyajima M et al: Prophylactic effect of papaverine prolonged-release pellets on cerebral vasospasm in dogs. Neurosurgery 42:109–116 1998

  • 19.

    Takamae TMizukami MKin Het al: Computed tomography of ruptured intracranial aneurysms in acute stage—relationship between vasospasm and high density on CT scan. Brain Nerve 30:8618661978Takamae T Mizukami M Kin H et al: Computed tomography of ruptured intracranial aneurysms in acute stage—relationship between vasospasm and high density on CT scan. Brain Nerve 30:861–866 1978

  • 20.

    Thomas JERosenwasser RHArmonda RAet al: Safety of intrathecal sodium nitroprusside for the treatment and prevention of refractory cerebral vasospasm and ischemia in humans. Stroke 30:140914161999Thomas JE Rosenwasser RH Armonda RA et al: Safety of intrathecal sodium nitroprusside for the treatment and prevention of refractory cerebral vasospasm and ischemia in humans. Stroke 30:1409–1416 1999

  • 21.

    Varsos VGLiszczak TMHan DHet al: Delayed cerebral vasospasm is not reversible by aminophylline, nifedipine, or papaverine in a “two-hemorrhage” canine model. J Neurosurg 58:11171983Varsos VG Liszczak TM Han DH et al: Delayed cerebral vasospasm is not reversible by aminophylline nifedipine or papaverine in a “two-hemorrhage” canine model. J Neurosurg 58:11–17 1983

  • 22.

    Visscher GERobinson RLMaulding HVet al: Biodegradation of and tissue reaction to 50:50 poly(DL-lactide-co-glycolide) microcapsules. J Biomed Mater Res 19:3493651985Visscher GE Robinson RL Maulding HV et al: Biodegradation of and tissue reaction to 50:50 poly(DL-lactide-co-glycolide) microcapsules. J Biomed Mater Res 19:349–365 1985

  • 23.

    Vollmer DGJane JSTorner JCet al: Intracisternal papaverine reverses experimental cerebral vasospasm in a rabbit model in Wilkins RH (ed): Cerebral Vasospasm. New York: Raven Press1988 pp 425432Vollmer DG Jane JS Torner JC et al: Intracisternal papaverine reverses experimental cerebral vasospasm in a rabbit model in Wilkins RH (ed): Cerebral Vasospasm. New York: Raven Press 1988 pp 425–432

  • 24.

    Weir BGrace MHansen Jet al: Time course of vasospasm in man. J Neurosurg 48:1731791978Weir B Grace M Hansen J et al: Time course of vasospasm in man. J Neurosurg 48:173–179 1978

  • 25.

    Wise DLSchwope ADHarrigan SEet al: Sustained delivery of a narcotic antagonist from lactic/glycolic acid copolymer implants in Kostelnik RJ (ed): Polymeric Delivery Systems. New York: Gordon and Breach Science1978 pp 7589Wise DL Schwope AD Harrigan SE et al: Sustained delivery of a narcotic antagonist from lactic/glycolic acid copolymer implants in Kostelnik RJ (ed): Polymeric Delivery Systems. New York: Gordon and Breach Science 1978 pp 75–89

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 81 81 15
Full Text Views 149 149 0
PDF Downloads 80 80 1
EPUB Downloads 0 0 0

PubMed

Google Scholar