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.

Occult rupture of a giant vertebral artery aneurysm following proximal occlusion and intrasaccular thrombosis. Case report.

The authors describe a unique clinicopathological phenomenon in a patient who presented with an unruptured giant vertebral artery aneurysm and who underwent endovascular proximal occlusion of the parent artery followed, several days later, by surgical trapping of the aneurysm after delayed subarachnoid hemorrhage (SAH). The intraoperative finding of a thrombus extruding from the wall of the aneurysm at a site remote from the origin of the SAH underscores the possibility that occult rupture of an aneurysmal sac can occur in patients with thrombosed giant aneurysms.

Results of combined stereotactic radiosurgery and transarterial embolization for dural arteriovenous fistulas of the transverse and sigmoid sinuses.

OBJECT: Most dural arteriovenous fistulas (DAVFs) of the transverse and sigmoid sinuses do not have angiographically demonstrated features associated with intracranial hemorrhage and, therefore, may be treated nonsurgically. The authors report their experience using a staged combination of radiosurgery and transarterial embolization for treating DAVFs involving the transverse and sigmoid sinuses. METHODS: Between 1991 and 1998, 25 patients with DAVFs of the transverse and/or sigmoid sinuses were treated using stereotactic radiosurgery; 22 of these patients also underwent transarterial embolization. Two patients were lost to follow-up review. Clinical data, angiographic findings, and follow-up records for the remaining 23 patients were collected prospectively. The mean duration of clinical follow up after radiosurgery was 50 months (range 20-99 months). The 18 women and five men included in this series had a mean age of 57 years (range 33-79 years). Twenty-two (96%) of 23 patients presented with pulsatile tinnitus as the primary symptom; two patients had experienced an earlier intracerebral hemorrhage (ICH). Cognard classifications of the DAVFs included the following: I in 12 patients (52%), IIa in seven patients (30%), and III in four patients (17%). After treatment, symptoms resolved (20 patients) or improved significantly (two patients) in 96% of patients. One patient was clinically unchanged. No patient sustained an ICH or irradiation-related complication during the follow-up period. Seventeen patients underwent follow-up angiographic studies at a mean of 21 months after radiosurgery (range 11-38 months). Total or near-total obliteration (> 90%) was seen in 11 patients (65%), and more than a 50% reduction in six patients (35%). Two patients experienced recurrent tinnitus and underwent repeated radiosurgery and embolization at 21 and 38 months, respectively, after the first procedure. CONCLUSIONS: A staged combination of radiosurgery and transarterial embolization provides excellent symptom relief and a good angiographically verified cure rate for patients harboring low-risk DAVFs of the transverse and sigmoid sinuses. This combined approach is a safe and effective treatment strategy for patients without angiographically determined risk factors for hemorrhage and for elderly patients with significant comorbidities.

Fatal progression of posttraumatic dural arteriovenous fistulas refractory to multimodal therapy. Case report.

The authors report the case of a man who suffered from progressive, disseminated posttraumatic dural arteriovenous fistulas (DAVFs) resulting in death, despite aggressive endovascular, surgical, and radiosurgical treatment. This 31-year-old man was struck on the head while playing basketball. Two weeks later a soft, pulsatile mass developed at his vertex, and the man began to experience pulsatile tinnitus and progressive headaches. Magnetic resonance imaging and subsequent angiography revealed multiple AVFs in the scalp, calvaria, and dura, with drainage into the superior sagittal sinus. The patient was treated initially with transarterial embolization in five stages, followed by vertex craniotomy and surgical resection of the AVFs. However, multiple additional DAVFs developed over the bilateral convexities, the falx, and the tentorium. Subsequent treatment entailed 15 stages of transarterial embolization; seven stages of transvenous embolization, including complete occlusion of the sagittal sinus and partial occlusion of the straight sinus; three stages of stereotactic radiosurgery; and a second craniotomy with aggressive disconnection of the DAVFs. Unfortunately, the fistulas continued to progress, resulting in diffuse venous hypertension, multiple intracerebral hemorrhages in both hemispheres, and, ultimately, death nearly 5 years after the initial trauma. Endovascular, surgical, and radiosurgical treatments are successful in curing most patients with DAVFs. The failure of multimodal therapy and the fulminant progression and disseminated nature of this patient's disease are unique.

Surgical repair of clinoidal segment carotid artery aneurysms unsuitable for endovascular treatment.

OBJECTIVE: Clinoidal segment carotid artery aneurysms are surgically challenging lesions. The aneurysm neck originates proximal to the distal dural ring, and the aneurysms typically are larger. Therefore, endovascular techniques are often considered to be the primary treatment option. Treatment techniques and results for 40 clinoidal segment carotid artery aneurysms that were considered unsuitable for contemporary endovascular intervention are analyzed in this report. METHODS: Forty aneurysms in 33 female and 3 male patients were treated surgically. Fifteen patients had bilateral aneurysms; of these patients, four underwent bilateral craniotomies. Twenty-seven aneurysms were 10 to 14 mm in size, eight were 15 to 24 mm, and five were more than 25 mm. The most common presentation was visual loss, which occurred in 13 patients. Seven patients presented with subarachnoid hemorrhage. RESULTS: Thirty-seven aneurysms were directly repaired with clipping, two were trapped with bypass, and one was trapped without bypass. The complication rate was 10%, with one major stroke, two minor strokes, and one successfully treated brain abscess. CONCLUSION: Surgical treatment of clinoidal segment carotid artery aneurysms can produce acceptable outcomes. Specific preoperative and intraoperative techniques facilitate improved surgical results for aneurysms that are not treatable with contemporary endovascular techniques.

Development of a cerebral arteriovenous malformation documented in an adult by serial angiography. Case report.

This 61-year-old man with a right-sided tentorial dural arteriovenous fistula (DAVF) was initially treated with staged stereotactic radiosurgery and transarterial embolization. Results of follow-up cerebral angiography performed 4 years later demonstrated complete obliteration of the dAVF and development of a previously undetected cerebellar arteriovenous malformation (AVM). The newly diagnosed AVM was treated with repeated stereotactic radiosurgery. This represents the first reported case of the development of a cerebral AVM documented in an adult by serial angiography.

Carotid cavernous fistula associated with persistent primitive trigeminal artery.

A patient with diplopia had a carotid cavernous fistula associated with a persistent primitive trigeminal artery that was seen with angiography. Balloon occlusion of the carotid cavernous fistula resulted in flow stasis of the persistent primitive trigeminal artery and resolution of the symptoms. Persistent primitive trigeminal artery may be associated with a carotid cavernous fistula.

Stereotactic radiosurgery and particulate embolization for cavernous sinus dural arteriovenous fistulae.

OBJECTIVE: To evaluate the safety and efficacy of stereotactic radiosurgery, either with or without transarterial embolization, in the treatment of patients with dural arteriovenous fistulae (DAVFs) of the cavernous sinus. METHODS: We reviewed the findings, from a prospectively established database, for 20 patients with cavernous sinus DAVFs who were treated with either radiosurgery alone (n = 7) or radiosurgery and transarterial embolization (n = 13) in a 7-year period. The median follow-up period after radiosurgery was 36 months (range, 4-59 mo). RESULTS: Nineteen of 20 patients (95%) experienced improvement of their clinical symptoms. Fourteen of 15 patients (93%) experienced either total (n = 13) or nearly total (n = 1) obliteration of their DAVFs, as documented by angiography performed a median of 12 months after radiosurgery. No patient experienced a recurrence of symptoms after angiography showed DAVF obliteration. Two patients developed new neurological deficits after embolization procedures. One patient exhibited temporary aphasia secondary to a venous infarction; another patient exhibited permanent VIth cranial nerve weakness related to acute cavernous sinus thrombosis. Two patients experienced recurrent symptoms and underwent repeat transarterial embolization at 7 and 12 months; both patients achieved clinical and angiographic cures (5 and 10 mo later, respectively). One patient experienced recurrent visual symptoms and underwent transvenous embolization 4 months after radiosurgery. CONCLUSION: Staged radiosurgery and transarterial embolization provided both rapid symptom relief and long-term cures for patients with cavernous sinus DAVFs. Radiosurgery alone was effective for patients with DAVFs whose arterial supply was not accessible via a transarterial approach, although the time course of symptom improvement was longer, compared with patients who also underwent embolization.

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.

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.

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).

Resection of a large temporooccipital parenchymal arteriovenous fistula by using deep hypothermic circulatory bypass. Case report.

The authors believe this to be the first published case in which a deep hypothermic cardiopulmonary bypass was used to facilitate resection of a large parenchymal arteriovenous fistula. The use of this procedure facilitated resection of the lesion by allowing compression and manipulation of large venous varices that were overlying the deeper arterial feeding vessels. The surgical rationale, technique, and intra- and postoperative management are discussed.

Endovascular treatment of ruptured posterior circulation aneurysms using electrolytically detachable coils.

The authors report their experience using electrolytically detachable coils for the treatment of ruptured posterior circulation aneurysms. Twenty-six patients with 28 posterior circulation aneurysms were treated. All patients were referred for endovascular treatment by experienced vascular neurosurgeons. Patients underwent follow-up angiography immediately after treatment, 1 to 6 weeks posttreatment, and 6 months posttreatment. Six-month follow-up angiograms obtained in 19 patients with 20 aneurysms demonstrated that 18 (90%) of the 20 aneurysms were 99 to 100% occluded, one aneurysm (5%) was approximately 90% occluded, and one aneurysm (5%) was approximately 75% occluded. The patient with the aneurysm that was approximately 75% occluded needed additional treatment, consisting of parent artery balloon occlusion, and was considered a treatment failure (3.8% of patients). There was one treatment-associated mortality (3.8%) but no treatment-associated serious neurological or nonneurological morbidity in the patient group. There was no recurrent aneurysm rupture during treatment or during the mean 27-month follow-up period. Endovascular treatment of ruptured posterior circulation aneurysms with electrolytically detachable coils can be accomplished with low morbidity and mortality rates. The primary goal of treatment--preventing recurrent aneurysm--can be achieved over the short term. Endovascular coil occlusion will play an important role in the treatment of ruptured posterior circulation aneurysms, particularly if long-term efficacy in preventing recurrent aneurysm hemorrhage can be documented.