An in silico 3D pharmacophore model of chalcones useful in the design of novel antimalarial agents.

Malaria, the most important of the human parasitic diseases, causes about 500 million infections worldwide and over 1 million deaths every year. The search for novel drug candidates against specific parasitic targets is an important goal for antimalarial drug discovery. Recently the antimalarial activity of chalcones has generated great interest. These compounds are small non-chiral molecules with relative high lipophilicity (clogP approximately 5-7), have molecular weights in the range of 300 to 600 g/mol, and possess in vivo efficacy against both P. berghei and P. yeolii. Preliminary data on our on-going chalcone synthesis project indicate that these compounds are active in vitro against P. falciparum, but are rapidly metabolized in liver microsome assays. Structurally-related compounds not including the enone linker are found to be much more metabolically stable and yet have comparable in vitro efficacy. In this study, we have utilized the efficacy data from an in-house on-going chalcone project to develop a 3D pharmacophore for antimalarial activity and used it to conduct virtual screening (in silico search) of a chemical library which resulted in identification of several potent chalcone-like antimalarials. The pharmacophore is found to contain an aromatic and an aliphatic hydrophobic site, one hydrogen bond donor site, and a ring aromatic feature distributed over a 3D space. The identified compounds were not only found to be potent in vitro against several drug resistant and susceptible strains of P. falciparum and have better metabolic stability, but included one with good in vivo efficacy in a mouse model of malaria.

Antileishmanial and antimalarial chalcones: synthesis, efficacy and cytotoxicity of pyridinyl and naphthalenyl analogs.

The antileishmanial and antimalarial activity of methoxy-substituted chalcones (1,3-diphenyl-2-propen-1-ones) is well established. The few analogs prepared to date where the 3-phenyl group is replaced by either a pyridine or naphthalene suggest these modifications are potency enhancing. To explore this hypothesis, sixteen 3-naphthalenyl-1-phenyl-2-prop-1-enones and ten 1-phenyl-3-pyridinyl-2-prop-1-enones were synthesized and their in vitro efficacies against Leishmania donovani and Plasmodium falciparum determined. One inhibitor with submicromolar efficacy against L. donovani was identified (IC50 = 0.95 microM), along with three other potent compounds (IC50 < 5 microM), all of which were 3-pyridin-2-yl derivatives. No inhibitors with submicromolar efficacy against P. falciparum were identified, though several potent compounds were found (IC50 < 5 microM). The cytotoxicity of the five most active L. donovani inhibitors was assessed. At best the IC50 against a primary kidney cell line was around two-fold higher than against L. donovani. Being more active than pentamidine, the 1-phenyl-3-pyridin-2-yl-2-propen-1-ones have potential for further development against leishmaniasis; however it will be essential in such a program to address not only efficacy but also their potential for toxicity.

Ocular motor nerve palsies in spontaneous dissections of the cervical internal carotid artery.

Cranial nerve palsies affecting ocular motor function in patients with spontaneous cervical internal carotid artery dissections are rare. Among 155 patients with spontaneous dissections of the cervical internal carotid artery, four (2.6%) had transient third, fourth, or sixth cranial nerve palsy. The third nerve was involved in two patients, the fourth nerve in one, and the sixth nerve in one. Three patients had ipsilateral headache or facial pain, one had bilateral headaches, and three had oculosympathetic palsy. None had any associated cerebral or retinal ischemic symptoms. Cervical internal carotid artery dissection should be included in the differential diagnosis of palsies of the third, fourth, or sixth cranial nerve, especially when associated with ipsilateral headache or facial pain. Interruption of the nutrient arteries supplying these cranial nerves could explain their involvement by internal carotid artery dissection.

Postoperative radiotherapy of supratentorial low-grade gliomas.

Forty-nine patients with supratentorial low-grade gliomas underwent surgery (biopsy or subtotal resection) and postoperative radiotherapy at the Mayo Clinic between 1976 and 1983. The median, 5-, and 10-year overall survivals for the total group were 6.5 years, 62%, and 14%, respectively. Nine prognostic variables were examined for their possible association with survival, including age, sex, site, size, CT enhancement, histologic type, extent of resection, radiation volume, and radiation dose. Of these variables, only histologic type was significantly associated with survival. The estimated 5-year survival was 100% for the 5 patients with pilocytic astrocytomas, 83% for the 20 patients with oligodendrogliomas or mixed oligo-astrocytomas, and 40% in the 24 patients with ordinary astrocytomas (log rank p = 0.001). Other possible prognostic variables, such as radiation volume or total dose, showed no association with survival. Twenty-seven patients had a documented treatment failure. For the 20 patients in whom the pattern of failure could be determined, all failed within their radiation portals. Eleven patients had additional tissue obtained following suspected disease recurrence. Tumor was found in ten of these patients, and radionecrosis in one.

Neodymium-YAG transscleral cyclophotocoagulation. The role of pigmentation.

Using a rabbit model we investigated the role of pigmentation of the ciliary body in obtaining ciliodestruction by neodymium-YAG transscleral cyclophotocoagulation. There was marked destruction of the ciliary body in pigmented rabbit eyes, but no histologic effect was observed in albino rabbit eyes. These findings suggest that pigmentation of the ciliary body is important for obtaining the desired response from neodymium-YAG transscleral cyclophotocoagulation in rabbit eyes by our technique. Further study is necessary to define the role of pigmentation in human eyes in this treatment modality.

Stereotactic radiosurgical treatment of cerebral arteriovenous malformations. Gamma Unit Radiosurgery Study Group.

OBJECTIVE: To assess the role of clinical factors, size of lesion, site of involvement, and radiation dose in patients with cerebral arteriovenous malformations (AVMs) who underwent stereotactic radiosurgical treatment. DESIGN: We reviewed the results in 121 patients with cerebral AVMs treated with the Leksell "Gamma Knife" between January 1990 and December 1993 at the Mayo Clinic in Rochester, Minnesota. MATERIAL AND METHODS: The following strict dose-volume protocol was used: AVMs 2.0 cm or smaller in diameter (volume, 4.2 cm3 or less) received 20 Gy to the margin of the nidus, those between 2.1 and 3.0 cm in diameter (4.3 to 14.1 cm3) received 18 Gy to the margin, and those that exceeded 3.0 cm in diameter (more than 14.1 cm3) received 16 Gy to the margin. Lesions that involved the brain stem received a radiosurgical dose of 18 Gy or less to the margin. Patients participated in regular follow-up clinical and imaging studies for up to 55 months. RESULTS: Follow-up cerebral angiography in 43 patients demonstrated total obliteration of the AVM nidus in 31 (72.1%), including 5 of 7 (71.4%) who had AVMs with a volume larger than 10 cm3. Clinical follow-up revealed that 111 patients (91.7%) had a stable or improved outcome, 3 had a nonfatal AVM hemorrhage, 2 suffered a fatal hemorrhage, and 2 died of causes not directly attributed to the AVM or radiosurgical treatment. Two patients had new or increased, nondisabling neurologic deficits as a result of treatment, and one patient had a temporary partial eyelid ptosis. CONCLUSION: Our findings suggest that previous theories about the relationship between AVM size and rate of obliteration after radiosurgical treatment may need revision. Our experience confirms that radiosurgical treatment for cerebral AVMs is safe and effective, even in cases for which the latency period before obliteration is longer than 2 years.

Medical and surgical management of intracranial aneurysms.

OBJECTIVE: To examine the medical and surgical aspects of intracranial aneurysms, including the pathogenesis, clinical manifestations, management of subarachnoid hemorrhage (SAH), and indications for surgical intervention. DESIGN: This review presents the classification of intracranial aneurysms, defines specific aneurysms, and analyzes the Mayo Clinic experience with surgical treatment of cerebral aneurysms. MATERIAL AND METHODS: Intracranial aneurysms are classified by cause, size, site, and shape. The clinical grading systems for SAH, the most common manifestation, are as follows: modified Botterell, Hunt and Hess, and World Federation of Neurological Surgeons. Surgical options are direct clipping, interventional neuroradiologic treatment, proximal ligation or trapping of aneurysms, and wrapping or coating of aneurysms. Although the timing of surgical intervention after SAH is controversial, it should be based on the clinical grade, site of the aneurysm, and patient's medical condition. RESULTS: The frequency of intracranial aneurysms is estimated to be 1 to 8% in the general population, and 90% of patients have SAH. After SAH, 8 to 60% of patients die before they get to a hospital. After hospitalization, the mortality rate is 37%, severe disability is 17%, and outcome is favorable in 47%. The current trend for surgical treatment is early after SAH. The Mayo Clinic experience with 1,947 patients who underwent surgical treatment because of aneurysmal SAH or for aneurysmal repair between 1969 and 1990 is as follows: 1,445 had an excellent outcome, 231 had a good outcome, 171 had a poor outcome, and 100 died. CONCLUSION: Aggressive management can be beneficial for many patients with severe neurologic injury after SAH by preventing rerupture of the aneurysm, attenuating the severity and sequelae of vasospasm, and decreasing the surgical complications.

Giant cell (temporal) arteritis: involvement of the vertebral and internal carotid arteries.

We report the radiographic findings in a case of histologically proven giant cell (temporal) arteritis coupled with high-grade stenoses affecting the internal carotid and vertebral arteries. The 69-year-old patient sought medical assessment because of transient ischemic attacks. The stenoses, which were extradural just proximal to the dural entry point, were thought to be a manifestation of the giant cell arteritis.

Percutaneous transcatheter embolization of coronary arteriovenous fistulas.

Coronary artery fistulas are infrequently encountered vascular communications that are either congenital or due to cardiac trauma. Most patients with these anomalies are asymptomatic, but late complications can occur and include congestive heart failure, myocardial ischemia, arrhythmias, and endocarditis. Therefore, many investigators have recommended surgical repair, even for asymptomatic patients. Although coronary arteriovenous fistulas pose many challenges to interventional cardiologists, early experiences suggest that these abnormal vessels can be successfully obliterated percutaneously; thus, the patient is spared the risks and morbidity associated with cardiac surgical intervention. Herein we present two cases that illustrate many of the technical issues involved in successful transcatheter embolization of coronary artery fistulas.

Prognostic significance of computed tomography of the brain in thrombotic thrombocytopenic purpura.

We studied the prognostic value of computed tomography (CT) of the brain for neurologic morbidity in patients with thrombotic thrombocytopenic purpura. On review of Mayo Clinic records for 1975 through 1985, we found 32 patients with thrombotic thrombocytopenic purpura, 20 of whom had undergone CT of the brain during their hospitalization. Despite major neurologic symptoms and signs, normal CT findings were associated with complete neurologic recovery. Seventy percent of patients with normal results of CT of the brain recovered and had no neurologic deficits, whereas 80% of patients with CT abnormalities died or had permanent neurologic sequelae. A review of the literature supports these conclusions. Thus, we suggest that CT of the brain be done in any patient with thrombotic thrombocytopenic purpura and neurologic deficits. Regardless of the severity of neurologic involvement, normal CT findings should encourage continued vigorous treatment of the patient because a normal scan supports the possibility of full clinical recovery.

Endovascular treatment of intracranial aneurysms.

OBJECTIVE: To examine the techniques, reported experiences, and advantages and disadvantages associated with the endovascular treatment of intracranial aneurysms. DESIGN: We review the endovascular techniques used for the treatment of intracranial aneurysms and the sequelae of subarachnoid hemorrhage, which have evolved during the past 10 years. MATERIAL AND METHODS: Two broad categories of endovascular therapy for intracranial aneurysms are described: occlusion of the parent artery and preservation of the parent artery by selective occlusion of the aneurysm with balloons or metallic coils. The Mayo protocol for testing tolerance of patients before permanent balloon occlusion of the parent artery is described, as are the types of aneurysms most amenable to this treatment. In addition, use of balloon angioplasty for cerebral vasospasm after subarachnoid hemorrhage is reviewed. RESULTS: Recent improvements in microcatheter technology have facilitated the safe navigation of percutaneously introduced catheters in the intracranial circulation and selective catheterization of intracranial aneurysms. Surgically difficult aneurysms are now being treated with endovascular techniques more frequently than in the past. Early results from animal experiments and human trials have shown that selective occlusion of aneurysms with metallic coils may have a role in the treatment of intracranial aneurysms. Balloon angioplasty of symptomatic cerebral vasospasm has demonstrated improvement in neurologic function in approximately 70% of patients. CONCLUSION: As technology continues to improve and as greater experience is obtained, interventional neuroradiologists will continue to have an increasingly important role in the treatment of intracranial aneurysms.

Intra-arterial thrombolysis in acute basilar artery thromboembolism: the initial Mayo Clinic experience.

OBJECTIVE: To investigate the feasibility of intra-arterial thrombolysis in acute basilar artery thrombosis. DESIGN: We reviewed a consecutive series of patients in whom intra-arterial thrombolysis was performed during the period from 1994 to 1996. MATERIAL AND METHODS: Intra-arterial thrombolysis with urokinase was done in an attempt to recanalize the basilar artery in a series of nine patients with basilar artery thrombosis admitted to the neurologic intensive care unit. At the time of initial assessment, all nine patients had major neurologic deficits attributable to brain-stem ischemia, including two patients with locked-in syndrome. RESULTS: Recanalization of the basilar artery system was successful in seven of the nine patients (a range of 2 to 13 hours after the ictus). Failure to recanalize the basilar artery occurred in two patients, who died after progressing to coma. Complete recovery or only minimal neurologic deficits were demonstrated in five of the nine patients. Despite recanalization of the basilar artery, two patients had no major change in their neurologic function, and both ultimately had severe ataxia and were fully dependent on others. A cerebellar hemorrhage occurred in one patient but without clinical worsening. Two patients had a retroperitoneal hematoma. CONCLUSION: Intra-arterial thrombolysis with urokinase in acute basilar artery occlusion resulted in recanalization in seven of the nine patients (78%). Five of the nine patients recovered fully, including two patients who had had locked-in syndrome. In light of the devastating natural course of acute basilar artery occlusion, these initial results are encouraging and indicate that intra-arterial thrombolysis may be a useful emergency treatment, even in patients with prolonged symptoms of ischemia (up to 12 hours).

Selective posterior cerebral artery injection of amytal: new method of preoperative memory testing.

The carotid Amytal test (Wada test) was introduced, in 1948 by Wada, to localize speech function before temporal lobectomy in patients with medically refractory epilepsy, and it remains the standard for that purpose. The same test has also been used since 1962 to evaluate memory function; however, the adequacy of the test in this application has been viewed with increasing skepticism in recent years. Therefore, we developed an alternative to the Wada test. It consists of selective injection of Amytal into the posterior cerebral artery (PCA). This PCA Amytal test is designed to test only memory function (not language). We present several anatomic and functional reasons why this approach should be superior to the Wada test for this purpose. We also present preliminary data in support of this hypothesis. To date, we have had successful results of the PCA Amytal test in 38 of 45 patients (84%), and one major complication has occurred (2%).

Cysts of Tenon's capsule following filtration surgery. Medical management.

Cysts of Tenon's capsule (encapsulated blebs) developed postoperatively in 77 (13%) of 607 eyes that underwent filtration surgery between 1980 and mid-1985. The annual incidence was not uniform, increasing markedly throughout the period. Seventy-four eyes were treated with medical therapy only. At a mean follow-up of 19 months, the success rate for these eyes, defined as an intraocular pressure (IOP) of 21 mm Hg or less, was 92%. The three eyes that underwent surgical revision subsequently failed clinically by the study criteria. Those patients in whom cysts of Tenon's capsule developed were compared with an age-matched control group to assess for possible differences in long-term outcome. There was a significantly higher IOP in the Tenon's cyst group at one and three months after surgery, and an increased proportion of IOPs above 30 and 40 mm Hg. At a six-month and later follow-up, there was no significant difference in the mean IOP or in progression of visual field loss. Causative factors were sought for the development of these cysts of Tenon's capsule. Prior conjunctival surgery, or previous cyst formation in the other eye, were the significant risk factors noted.

Extracapsular cataract extraction and posterior chamber intraocular lens implantation combined with trabeculectomy in patients with glaucoma.

We reviewed 75 consecutive cases of extracapsular cataract extraction and posterior chamber intraocular lens implantation combined with trabeculectomy in 69 patients with glaucoma. The mean preoperative intraocular pressure was 19.3 mm Hg on an average of 2.3 glaucoma medications. Visual acuity improved in 58 eyes (77%) at two months, with an average improvement of 3.3 and 3.6 lines at two and 12 months, respectively. Of the 75 eyes, 49 (65%) achieved a visual acuity of 20/40 or better; three patients (4%) had further deterioration in vision at the completion of follow-up because of progressive glaucoma or macular disease. Postoperatively, the average intraocular pressure was 3.8 and 3.0 mm Hg lower than the preoperative level at two and 12 months (P less than .001) on 0.63 and 0.79 glaucoma medications, respectively. However, 27 (36%) of the 75 eyes had a recorded intraocular pressure greater than 30 mm Hg and 30 (40%) had a pressure 7 mm Hg or more above their preoperative level during the first six months after surgery. Despite improved long-term control of intraocular pressure, detectable conjunctival filtering blebs were present in only 31 (41%) of 75 eyes at two months and in seven (12%) of 56 eyes at 12 months. Hyphema occurred in 34 (45%) of the cases.

Embolization of spinal dural arteriovenous fistula with polyvinyl alcohol particles: experience in 14 patients.

PURPOSE: To assess the effectiveness, initial and long term, of embolization using polyvinyl alcohol particles (PVA) particles in patients with spinal dural arteriovenous fistulas (SDAVF). METHODS: The initial treatment in 14 patients with SDAVF was embolization with PVA particles. Postembolization occlusion of the SDAVF was documented angiographically in all cases. RESULTS: All 14 patients initially showed an improvement in clinical symptoms, but the neurologic status of 11 patients subsequently deteriorated. Of the 11 patients who had recurrence of symptoms, nine had angiographically proven recurrences of their SDAVF while two had negative follow-up of spinal angiography. PVA embolization is ineffective for the treatment of SDAVF and is not without risk. CONCLUSION: On the basis of a literature review of the other two alternative treatments (operation or liquid adhesive embolization) available for SDAVF and our preliminary experience with N-butyl cyanoacylate (NBCA) embolization, we suggest that NBCA embolization be the initial treatment of choice for SDAVF; if that procedure is not possible, or is unsuccessful, then operation is recommended.

Blinded prospective evaluation of sensitivity of MR angiography to known intracranial aneurysms: importance of aneurysm size.

PURPOSE: To determine the sensitivity of time-of-flight and phase-contrast MR angiography for the detection of intracranial aneurysms. METHODS: Sixteen patients with 27 intracranial aneurysms previously identified with conventional angiography and 19 control patients were examined with three-dimensional time-of-flight, three-dimensional phase-contrast MR angiography, and standard MR imaging. Subvolumes of the carotid and posterior circulations, source images, and standard MR images were blindly interpreted by three experienced neuroradiologists. RESULTS: Detection of an aneurysm by a given sequence was defined as at least two of the three blinded readers identifying the aneurysm. The sensitivities of the sequences based on all 27 aneurysms were: transaxial T1, 25.9%; T2, 48.1%; PC, 44.4%; and TF, 55.6%. Two of 3 aneurysms detected with T2 but not MR angiography had adjacent blood products. Five millimeters appeared to be a critical size; the sensitivities for aneurysms greater than or equal to 5 mm were: T1, 37.5%; T2, 62.5%; PC, 75%; and TF, 87.5%. CONCLUSIONS: Three-dimensional time-of-flight MR with 512 x 256 matrix is more sensitive than three-dimensional phase-contrast or standard MR imaging for detection of aneurysms. Retrospectively, aneurysms 3 mm or larger can be identified with MR angiography; however, prospectively, 5 mm is the critical size for detection.

MR angiographic and sonographic indications for endarterectomy.

PURPOSE: Our objective was to determine whether appropriate criteria could be developed for performing an endarterectomy on the basis of sonographic and MR angiographic findings. METHODS: Fifty patients were examined prospectively with sonography, MR angiography, and conventional angiography. All three imaging studies were performed within 2 weeks of one another, and conventional angiography served as the reference standard. RESULTS: All 10 carotid occlusions were detected with sonography and MR angiography. Sonography accurately showed flow in two arteries, and MR angiography showed flow in one of three nearly occluded arteries with extremely slow flow. Multislab three-dimensional time-of-flight MR angiographic sequences underestimated the degree of stenosis in 12 arteries, and in two cases this resulted from high T1 signal within the atherosclerotic plaque. With conventional angiography as the reference standard for 70% to 99% stenosis, sonography had a sensitivity of 96%, a specificity of 91%, and a positive predictive value of 90%, while concordant sonographic findings and the presence of a signal void on multislab 3-D time-of-flight sequences had a sensitivity of 72%, a specificity of 98%, and a positive predictive value of 97%. CONCLUSION: Endarterectomy performed on the basis of sonographic findings of 70% to 99% stenosis and of a signal void on multislab 3-D time-of-flight MR angiographic sequences is appropriate.

Preliminary report: effects of high dose methylprednisolone on delayed cerebral ischemia in patients at high risk for vasospasm after aneurysmal subarachnoid hemorrhage.

Mounting evidence suggests that chronic cerebral vasospasm may be linked to the inflammatory response that follows subarachnoid hemorrhage. Twenty-one patients judged to be at high risk for vasospasm because of either poor admitting grade or a large amount of subarachnoid blood shown by computed tomography were treated with a course of high dose methylprednisolone, and management results were compared to those of a cohort of contemporary control patients matched for grade, number of hemorrhages, time from hemorrhage to admission, time from hemorrhage to operation, aneurysm location, age, and sex. Patients treated with high dose methylprednisolone were twice as likely to have an excellent result and half as likely to die as those who were not treated. The incidence and severity of delayed cerebral ischemia were reduced in treated patients when compared to control patients. None of the treated patients developed a serious side effect that could be attributed to steroid treatment. These findings are consistent with the conclusion that chronic vasospasm is an inflammatory vasculopathy and suggest that early treatment with high dose methylprednisolone may benefit this high risk group of patients.

Childhood dural arteriovenous fistulae of the posterior dural sinuses: three case reports and literature review.

We report three cases of posterior dural sinus arteriovenous fistulae in pediatric patients and a literature review of 18 additional cases. These lesions carry a grave prognosis with a reported mortality of 38% and with an historical anatomic cure of only approximately 9%. With advanced neurointerventional techniques and increased knowledge of their pathophysiology, these highly complicated lesions can be more safely treated with a strategy that involves extensive preoperative embolization and surgical excision. The importance of delaying direct surgery with conservative measures or interventional radiological treatment, including preoperative transarterial and transvenous embolization, is critical in the management of these lesions.