Can Young Vascular Neurosurgeons Become Proficient in Microsurgical Clip Reconstruction in the Endovascular Era? A Rotterdam Cohort Spanning 2 Decades with Propensity Score Matching for Complexity.

BACKGROUND: Little is known about the results of young vascular neurosurgeons who perform only microsurgical clip reconstruction in the era since the International Subarachnoid Aneurysm Trial (ISAT) or about the training and caseload required to equivocate the results of senior, more experienced colleagues. The aim of this study was to compare clinical outcomes of patients treated by young and senior vascular neurosurgeons at Erasmus MC University Medical Center Rotterdam, adjusting for case mix. METHODS: A partially prospective and partially retrospective database was used. Hierarchical mixed models with a random intercept for surgeon were used for confounder adjustment, and propensity score matching for complexity was used to create comparable groups. RESULTS: The study included 609 patients harboring 767 aneurysms. Most (86%) of the aneurysms had at least 1 complexity characteristic, with the majority having 3 characteristics. The most often encountered complexity characteristics were the presence of a broad neck and the presence of branches emerging from the aneurysm. Use of temporary clipping and skull base approaches was significantly higher in the young vascular neurosurgeons group (P < 0.0001). The complexity score differed significantly between senior and young vascular neurosurgeons (P < 0.001). After propensity score matching for complexity, multivariable logistic regression showed young vascular neurosurgeons to be significantly associated with better outcomes for ruptured aneurysms (propensity score weighted odds ratio 0.55 [95% confidence interval 0.35-0.88], P = 0.01). CONCLUSIONS: In a high-volume neurovascular center where both endovascular and microsurgical treatment options are available, young vascular neurosurgeons can be trained to achieve at least the same results as their senior colleagues despite increased complexity.

Organ donation as transition work: Policy discourse and clinical practice in The Netherlands.

An increasing number of patients become eligible for organ transplants. In the Netherlands, at the level of policy discourse, growing waiting lists are often referred to as a persistent "shortage" of organs, producing a "public health crisis." In this way, organ donation is presented as an ethical, social, and medical necessity. Likewise, policy discourse offers a range of seemingly unambiguous solutions: improving logistical infrastructure at the level of hospitals, developing organizational and legal protocols, as well as public information campaigns. Instead of taking these problem and solution definitions as given, we critically examine the relationship between policy discourse and clinical practice. Based on a historical review, first, we trace the key moments of transformation where organ donation became naturalized in Dutch policy discourse, particularly in its altruistic connotation. Second, based on in-depth interviews with medical professionals, we show how those involved in organ donation continue to struggle with the controversial nature of their clinical practice. More specifically, we highlight their use of different forms of knowledge that underlie clinicians' "transition work": from losing a patient to "gaining" a donor.

Physical therapy plus general practitioners' care versus general practitioners' care alone for sciatica: a randomised clinical trial with a 12-month follow-up.

A randomised clinical trial in primary care with a 12-months follow-up period. About 135 patients with acute sciatica (recruited from May 2003 to November 2004) were randomised in two groups: (1) the intervention group received physical therapy (PT) added to the general practitioners' care, and (2) the control group with general practitioners' care only. To assess the effectiveness of PT additional to general practitioners' care compared to general practitioners' care alone, in patients with acute sciatica. There is a lack of knowledge concerning the effectiveness of PT in patients with sciatica. The primary outcome was patients' global perceived effect (GPE). Secondary outcomes were severity of leg and back pain, severity of disability, general health and absence from work. The outcomes were measured at 3, 6, 12 and 52 weeks after randomisation. At 3 months follow-up, 70% of the intervention group and 62% of the control group reported improvement (RR 1.1; 95% CI 0.9-1.5). At 12 months follow-up, 79% of the intervention group and 56% of the control group reported improvement (RR 1.4; 95% CI 1.1; 1.8). No significant differences regarding leg pain, functional status, fear of movement and health status were found at short-term or long-term follow-up. At 12 months follow-up, evidence was found that PT added to general practitioners' care is only more effective regarding GPE, and not more cost-effective in the treatment of patients with acute sciatica than general practitioners' care alone. There are indications that PT is especially effective regarding GPE in patients reporting severe disability at presentation.

Occurrence of malignant vertebral fractures in an emergency room setting.

BACKGROUND: To perform a risk analysis study to determine the probability of a spinal fracture being of malignant origin in patients presenting at a level I trauma centre emergency room after trauma. PATIENTS AND METHODS: Data from 334 consecutive patients were retrospectively obtained from 1993 to 2003. They were divided into two groups: group 1--(benign) traumatic fractures; and group 2--malignant fractures (n = 32). For statistical analysis independent Student t test, chi2 test, and backward-stepwise logistic regression were used. RESULTS: The risk of vertebral fractures appearing to be of malignant origin increased with anatomical location (non-cervical--that is, thoracic or lumbar: odds ratio (OR) 48, 95% confidence interval (CI) 8 to 291), a history of malignancy (OR 72, 95% CI 12 to 422), trauma mechanism (that is, high energy: OR 0.03, 95% CI 0.003 to 0.28), and age >64 years (OR 3, 95% CI 0.9 to 12). Hence, patients over 64 years old attending the emergency room, with a vertebral fracture after a low energy trauma, had an approximately 50% chance of having a malignant fracture. With a non-cervical location and a history of malignancy this increased to 98%. Regardless of the trauma mechanism and age of the patient, a history of a malignancy and a non-cervical fracture posed at least a 36% risk of having a malignant fracture. CONCLUSION: Supported by the present results we feel the probability of malignant fractures, although not frequently encountered, should always be considered in elderly and middle-aged patients with a history of malignancy and a non-cervical traumatic fracture.

Cost-effectiveness of physical therapy and general practitioner care for sciatica.

STUDY DESIGN: An economic evaluation alongside a randomized clinical trial in primary care. A total of 135 patients were randomly allocated to physical therapy added to general practitioners' care (n = 67) or to general practitioners' care alone (n = 68). OBJECTIVE: To evaluate the cost-effectiveness of physical therapy and general practitioner care for patients with an acute lumbosacral radicular syndrome (LRS, also called sciatica) compared with general practitioner care only. SUMMARY OF BACKGROUND DATA: There is a lack of knowledge concerning the cost-effectiveness of physical therapy in patients with sciatica. METHODS: The clinical outcomes were global perceived effect and quality of life. The direct and indirect costs were measured by means of questionnaires. The follow-up period was 1 year. The Incremental Cost-effectiveness Ratio (ICER) between both study arms was constructed. Confidence intervals for the ICER were calculated using Fieller's method and using bootstrapping. RESULTS: There was a significant difference on perceived recovery at 1-year follow-up in favor of the physical therapy group. The additional physical therapy did not have an incremental effect on quality of life. At 1-year follow-up, the ICER for the total costs was 6224 euros (95% confidence interval, -10,419, 27,551) per improved patient gained. For direct costs only, the ICER was 837 euros (95% confidence interval, -731, 3186). CONCLUSION: The treatment of patients with LRS with physical therapy and general practitioners'care is not more cost-effective than general practitioners'care alone.

Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries.

Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 microM), the neurokinin NK1 receptor antagonist L-733060 (0.5 microM), the voltage-sensitive calcium channel blocker ruthenium red (100 microM), the TRPV1 receptor antagonist capsazepine (5 microM), the nitric oxide synthetase inhibitor Nomega-nitro-L-arginine methyl ester HCl (L-NAME; 100 microM), the gap junction blocker 18alpha-glycyrrhetinic acid (10 microM), as well as the RhoA kinase inhibitor Y-27632 (1 microM). Further, we also used the K+ channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 microM) + apamin (0.1 microM) and iberiotoxin (0.5 microM) + apamin (0.1 microM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) alpha-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK1, NO, vanilloid receptors, voltage-sensitive calcium channels, K+ channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism.

Characterisation of CGRP receptors in the human isolated middle meningeal artery.

Although the understanding of migraine pathophysiology is still incomplete, there seems to be little doubt that dilatation of cranial blood vessels, including meningeal arteries, is involved in the headache phase of migraine. Since calcitonin gene-related peptide (CGRP) has been implicated in this vasodilatation, the present study set out to compare the relaxant effects of the endogenous ligand h-alphaCGRP, and [ethylamide-Cys(2,7)]h-alphaCGRP ([Cys(Et)(2,7)]h-alphaCGRP), a CGRP(2) receptor agonist, on human isolated middle meningeal artery segments, precontracted with KCl. Classical Schild plot analysis was used to characterise the receptor population in this artery using BIBN4096BS and h-alphaCGRP(8-37) as antagonists. h-alphaCGRP relaxed arterial segments more potently than [Cys(Et)(2,7)]h-alphaCGRP (pEC(50): 8.51+/-0.16 and 7.48+/-0.24, respectively), while the maximal responses to these agonists were not significantly different. BIBN4096BS equipotently blocked the relaxations induced by both agonists with a pA(2) of approximately 10 and with a Schild plot slope not significantly different from unity. h-alphaCGRP(8-37) also antagonised the response to h-alphaCGRP with a pA(2) of 6.46+/-0.16 and a Schild plot slope not different from unity. Furthermore, the results obtained from RT-PCR studies confirmed the presence of all the essential components required for a functional CGRP(1) receptor in these arteries. Considering the high antagonist potency of BIBN4096BS, coupled to the lower agonist potency of [Cys (Et)(2,7)]h-alphaCGRP, it is reasonable to suggest a predominant role of CGRP(1) receptors in the human middle meningeal artery. This view is reinforced by Schild plot analysis, which revealed a slope of unity in all experiments, giving further evidence for a homogeneous CGRP receptor population in this vascular preparation.

Identification of relevant prognostic histopathologic features in 69 intracranial ependymomas, excluding myxopapillary ependymomas and subependymomas.

BACKGROUND: The results of attempts to identify histopathologic parameters that contribute to the clinical outcome of patients with ependymomas have been controversial. This may be due to the relative rareness of ependymomas. Furthermore, in many investigations, myxopapillary ependymomas and subependymomas were included and may have confounded results, because those tumors should be considered clinicopathologic entities distinct from the other ependymomas. METHODS: In this retrospective study, the influence of the histologic subtype of ependymoma and of individual histologic features on the outcome of 69 patients with ependymomas was investigated. Myxopapillary ependymomas, subependymomas, and ependymomas with spinal localizations were excluded from the analysis. The ependymomas were subdivided into cellular, papillary, clear cell, and tanycytic subtypes. The study extended over a period of 30 years. RESULTS: No differences in clinical outcome between the four histologic subtypes of ependymomas were revealed. Neither tumor localization (either infratentorial or supratentorial), patient age, nor gender affected survival. The survival of patients who underwent complete tumor resection differed significantly from that of patients who underwent partial resection. In univariate analysis, the features of nuclear atypia, the mitotic index, and the MIB-1 labeling index (LI) significantly influenced survival. With regard to survival, the presence of microcysts, blood vessel density, and the feature of vascular hyalinization demonstrated a trend but did not reach significance. In multivariate analysis, only the mitotic index and the MIB-1 LI were identified as factors with independent prognostic significance (P = 0.027 and P = 0.023, respectively). Both proliferation indices were correlated strongly with each other. CONCLUSIONS: The results of the univariate analysis indicated that, for patients with intracranial ependymoma, nuclear atypia, the mitotic index, and the MIB-1 LI significantly influenced survival. In the multivariate analysis, the mitotic index and the MIB-1 LI were the only features that had independent prognostic significance. Because both showed strong correlations, only one of them should be included in a grading scheme for intracranial ependymomas.

Low-molecular weight caldesmon as a potential serum marker for glioma.

PURPOSE: Testing the feasibility of using the serum low-molecular weight caldesmon (l-CaD) level as a serum marker for the presence of glioma. EXPERIMENTAL DESIGN: Within a total of 230 serum samples, the l-CaD level was measured in healthy volunteers (30), patients with gliomas (57), nonglial intracranial tumors (107), and nontumor neurologic diseases (36) by ELISA. The specificity of the assay was monitored by combination of immunoprecipitation and immunoblotting. RESULTS: The serum level of l-CaD is significantly higher in the group of glioma patients as compared with any of the other groups (P < 0.001). The cutoff value of 45 yields optimal sensitivity and specificity of the assay (91% and 84%, respectively; area under the curve score = 0.91). The specificity of ELISA was confirmed by the immunoprecipitation/immunoblotting control experiments. There were no significant differences in serum l-CaD levels between patients with low- or high-grade gliomas. CONCLUSIONS: The serum l-CaD level as determined by ELISA is a good discriminator between glioma patients versus patients with other intracranial tumors, other neurologic diseases, and healthy people. Prospective studies are required to test the contribution of the assay in making the diagnosis of glioma, or its feasibility for monitoring the tumor during treatment.

Chromosomal instability in meningiomas.

Approximately 60% of sporadic meningiomas are caused by inactivation of the NF2 tumor suppressor gene on chromosome 22. No causative gene is known for the remaining 40%. Cytogenetic analysis shows that meningiomas caused by inactivation of the NF2 gene can be divided into tumors that show monosomy 22 as the sole abnormality and tumors with a more complex karyotype. Meningiomas not caused by the NF2 gene usually have a diploid karyotype. Here we report that, besides the clonal chromosomal aberrations, the chromosome numbers in many meningiomas varied from one metaphase spread to the other, a feature that is indicative of chromosomal instability. Unexpectedly and regardless of genotype, a subgroup of tumors was observed with an average number of 44.9 chromosomes and little variation in the number of chromosomes per metaphase spread. In addition, a second subgroup was recognized with a hyperdiploid number of chromosomes (average 48.5) and considerable variation in numbers per metaphase. However, this numerical instability resulted in a clonal karyotype with chromosomal gains and losses in addition to loss of chromosome 22 only in meningiomas caused by inactivation of the NF2 gene. In cultured cells of all tumor groups, bi- and multinucleated cells were seen, as well as anaphase bridges, residual chromatid strings, multiple spindle poles, and unseparated chromatids, suggesting defects in the mitotic apparatus or kinetochore. Thus, we conclude that even a benign and slow-growing tumor like a meningioma displays chromosomal instability.

General practitioners' management of lumbosacral radicular syndrome compared with a clinical guideline.

OBJECTIVE: To investigate the current treatment policy of general practitioners (GPs) in patients with a lumbosacral radicular syndrome (LRS) compared with their clinical guideline. DESIGN: A cross sectional survey. METHODS: Sixty-three GPs completed questionnaires about their treatment policy in individual LRS patients at baseline and at six months follow-up. Simultaneously, 136 LRS patients of these GPs were interviewed at baseline, and at three and six month's follow-up. RESULTS: Of the 12 recommendations in the guideline related to history taking, four were not adhered to by the GPs in about 25% of the patients. Of the ten recommended physical examinations, three are not frequently carried out by the GPs. Almost 40% of the patients were referred to physiotherapy and 27% received muscle relaxants. CONCLUSION: The majority of the GPs support the content of the LRS guideline. Overall, there was a good adherence with the guideline for history taking and physical examination, and a moderate adherence for treatment policy.

Conservative treatment in patients with an acute lumbosacral radicular syndrome: design of a randomised clinical trial [ISRCTN68857256].

BACKGROUND: The objective is to present the design of randomised clinical trial (RCT) on the effectiveness of physical therapy added to general practitioners management compared to general practitioners management only in patients with an acute lumbosacral radicular syndrome (also called sciatica). METHODS/DESIGN: Patients in general practice diagnosed with an acute (less than 6 weeks) lumbosacral radicular syndrome and an age above 18 years are eligible for participation. The general practitioners treatment follows their clinical guideline. The physical therapy treatment will consist of patient education and exercise therapy. The primary outcome measure is patients reported global perceived effect. Secondary outcome measures are severity of complaints, functional status, health status, fear of movement, medical consumption, sickness absence, costs and treatment preference. The follow-up is 52 weeks. DISCUSSION: Treatment by general practitioners and physical therapists in this study will be transparent and not a complete "black box". The results of this trial will contribute to the decision of the general practitioner regarding referral to physical therapy in patients with an acute lumbosacral radicular syndrome.

Neurosurgeons' management of lumbosacral radicular syndrome evaluated against a clinical guideline.

To establish to what extent neurosurgeons subscribe to the lumbosacral radicular syndrome (LRS) guideline, and to evaluate their current management of patients with LRS against the guideline. All active neurosurgeons in the Netherlands (n=92) were mailed a questionnaire about the guideline and data from 66 responders were analysed. Patients were recruited via seven of the participating neurosurgeons and were interviewed once by telephone. The medical records of the participating patients (n=163) were also examined. Of the 26 propositions in the LRS guideline, seven were not fully endorsed by the neurosurgeons. Three of these seven propositions may need updating based on "new evidence". The time between the onset of the LRS episode and the actual moment of surgery was considerably longer than that recommended in the guideline. Based on their current management of LRS patients, the neurosurgeons largely adhere with the LRS guideline.

Identification of tumor-related proteins by proteomic analysis of cerebrospinal fluid from patients with primary brain tumors.

Cerebrospinal fluid (CSF) has been rediscovered in the post-genomic era as a great source of potential protein biomarkers for various diseases. The source allows rapid screening, low sample consumption, and accurate protein identification by proteomic technology. In the present study, we identified 2 candidate tumor-related proteins, N-myc oncoprotein and low-molecular weight caldesmon (l-CaD), in CSF samples of patients with primary brain tumors by using 2-dimensional polyacrylamide gel electrophoresis (2D PAGE), followed by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) analysis. N-myc and l-CaD were related to tumor cell nuclei and blood vessels, respectively, in tissue sections of the tumor biopsies taken from the same patients from whom CSF was processed. N-myc oncoprotein and l-CaD have not been detected in CSF before. The practical value of these proteins as possible tumor markers, prognosticators, or their utility in monitoring response to chemotherapy is currently a subject of investigation. It is concluded that the combination of 2D PAGE and MALDI-TOF-MS is successful as an unbiased global screening tool for CSF.

Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir.

Between November 1998 and December 2001, we treated 14 patients with advanced recurrent high-grade gliomas with a total dose of 4.6 x 10(8), 4.6 x 10(9), 4.6 x 10(10), or 4.6 x 10(11) viral particles (VP) of a replication-incompetent adenoviral vector harboring the herpes simplex virus thymidine kinase gene driven by the adenoviral major late promoter (IG.Ad.MLPI.TK), followed by ganciclovir (GCV) treatment. The VP-to-infectious-unit ratio was 40. The vector was administered by 50 intraoperative wound-bed injections of 0.2 ml each (total volume 10 ml). The study's primary objective was to determine the safety of this treatment and establish the maximum tolerated dose (MTD). Injection of all doses of IG.Ad.MLPI.TK followed by GCV was safely tolerated and MTD was not reached. All patients had recurrence or progression of the tumor 1-24 months (median 3.5 months) after gene therapy. The overall median survival was 4 months. Four patients survived longer than 1 year following gene therapy. One patient is still alive, with histologically confirmed progression of the tumor, 29 months after treatment. Ten patients died within 8 months of treatment, all from progression of the tumor. In 5 patients residual and measurable tumor was visible on the direct (<48 h) postoperative MRI. No objective radiological response was documented on subsequent MRI. None of the patients came to autopsy. In conclusion, the administration of 4.6 x 10(11) VP of IG.Ad.MLPI.TK by 50 injections into the wound bed following resection of recurrent malignant glioma, followed by GCV treatment, was well tolerated.

Imaging expression of adenoviral HSV1-tk suicide gene transfer using the nucleoside analogue FIRU.

Substrates for monitoring HSV1-tk gene expression include uracil and acycloguanosine derivatives. The most commonly used uracil derivative to monitor HSV1-tk gene transfer is 1-(2-fluoro-2-deoxy--D-arabinofuranosyl)-5-[*I]iodouracil (fialuridine; I*-FIAU), where the asterisk denotes any of the radioactive iodine isotopes that can be used. We have previously studied other nucleosides with imaging properties as good as or better than FIAU, including 1-(2-fluoro-2-deoxy--D-ribofuranosyl)-5-[*I]iodouracil (FIRU). The first aim of this study was to extend the biodistribution data of 123I-labelled FIRU. Secondly, we assessed the feasibility of detecting differences in HSV1-tk gene expression levels following adenoviral gene transfer in vivo with 123I-FIRU. 9L rat gliosarcoma cells were stably transfected with the HSV1-tk gene (9L-tk+). 123I-FIRU was prepared by radioiodination of 1-(2-fluoro-2-deoxy--D-ribofuranosyl)-5-tributylstannyl uracil (FTMRSU; precursor compound) and purified using an activated Sep-Pak column. Incubation of 9L-tk+ cells and the parental 9L cells with 123I-FIRU resulted in a 100-fold higher accumulation of radioactivity in the 9L-tk+ cells after an optimum incubation time of 4 h. NIH-bg-nu-xid mice were then inoculated subcutaneously with HSV1-tk (-) 9L cells or HSV1-tk (+) 9L-tk+ cells into both flanks. Biodistribution studies and gamma camera imaging were performed at 15 min and 1, 2, 4 and 24 h p.i. At 15 min, the tumour/muscle, tumour/blood and tumour/brain ratios were 5.2, 1.0 and 30.3 respectively. Rapid renal clearance of the tracer from the body resulted in increasing tumour/muscle, tumour/blood and tumour/brain ratios, reaching values of 32.2, 12.5 and 171.6 at 4 h p.i. A maximum specific activity of 22%ID/g tissue was reached in the 9L-tk+ tumours 4 h after 123I-FIRU injection. Two Ad5-based adenoviral vectors containing the HSV1-tk gene were constructed: a replication-incompetent vector with the transgene in the former E1 region, driven by a modified CMV promoter, and a novel replication-competent vector with the HSV1-tk gene in E3 driven by the natural E3 promoter. The human glioma cell lines U87MG and T98G were infected with a multiplicity of infection (m.o.i.) of 10. Forty-eight hours later the cells were incubated with 123I-FIRU and radioactivity was measured in a gamma counter. We found significantly higher levels of radioactivity in both cell lines following infection with the replication-competent vector (P<0.001). NIH-bg-nu-xid mice were then inoculated subcutaneously with U87MG cells. Tumours (approximately 1,000 mm3) were injected with 108 and 109 Infectious Units (I.U.) of either vector. After 48 h, the tracer was injected, followed by gamma camera imaging and direct measurement of radioactivity in the tumours at 4 h p.i. Images and direct measurements indicated increased uptake of tracer with higher I.U. and also demonstrated increased accumulation of tracer in the tumours treated with the replication-competent adenoviral vector (P=0.03). These results demonstrate that 123I-FIRU in combination with HSV1-tk is a valuable tracer for in vivo monitoring of adenoviral gene transfer.

Comparison of contractile responses to donitriptan and sumatriptan in the human middle meningeal and coronary arteries.

Donitriptan is a potent, high efficacy agonist at 5-HT(1B/1D) receptors. We investigated the contractile effects of donitriptan and sumatriptan on human isolated blood vessels of relevance to therapeutic efficacy in migraine (middle meningeal artery) and coronary adverse events (coronary artery). Furthermore, using the concentration-response curves in the middle meningeal artery, we predicted the plasma concentration needed for the therapeutic effect of donitriptan. Both donitriptan and sumatriptan contracted the middle meningeal artery with similar apparent efficacy (E(max): 103+/-8% and 110+/-12%, respectively), but the potency of donitriptan (pEC(50): 9.07+/-0.14) was significantly higher than that of sumatriptan (pEC(50): 7.41+/-0.08). In the coronary artery, the contraction to donitriptan was biphasic with a significantly higher maximal response (E(max): 29+/-6%) than sumatriptan (E(max): 14+/-2%; pEC(50): 5.71+/-0.16), yielding two distinct pEC(50) values (8.25+/-0.16 and 5.60+/-0.24). Incubation with the 5-HT(2) receptor antagonist ketanserin (10 microM) eliminated the low affinity component of the concentration-response curve of donitriptan and the resultant E(max) and pEC(50) were 9+/-2% and 7.33+/-0.21, respectively. Ketanserin was without effect on the sumatriptan-induced contraction. Based on the middle meningeal artery contraction, concentrations (C(max)) of donitriptan that may be expected to have a therapeutic efficacy equivalent to that of 50 and 100 mg sumatriptan are predicted to be around 2.5 and 4.3 nM, respectively. Such concentrations are likely to induce only a small coronary artery contraction of 2.9+/-1.5% and 3.8+/-2.0%, respectively; these are not different from those by C(max) concentrations of sumatriptan (1.7+/-0.4% or 2.2+/-0.4%). The present results suggest that, like sumatriptan, donitriptan exhibits cranioselectivity and would be effective in aborting migraine attacks with a similar coronary side-effect profile as sumatriptan.