Intracerebroventricular bethanechol for Alzheimer's disease. Variable dose-related responses.

Five male patients participated in a pilot open-label study of dose-related aspects of response to intracerebroventricular bethanechol in Alzheimer's disease. No patient had remission of symptoms, but three patients improved symptomatically and on tests of memory. Improvement was evident over a restricted range of doses for each subject, and symptoms were worse at doses below and above the optimal range. There was little overlap in the range of doses producing improvement among these three. Two patients had no consistent improvement in memory, and agitation, depression, paranoia, and seizures developed during treatment. Qualitative differences and variability in dosages producing responses complicate the identification of true drug response in the treatment of Alzheimer's disease.

Diffusion-perfusion MR evaluation of perihematomal injury in hyperacute intracerebral hemorrhage.

BACKGROUND: It has been suggested that a zone of perihematomal ischemia analogous to an ischemic penumbra exists in patients with primary intracerebral hemorrhage (ICH). Diffusion-perfusion MRI provides a novel means of assessing injury in perihematomal regions in patients with ICH. OBJECTIVE: To characterize diffusion-perfusion MRI changes in the perihematomal region in patients with hyperacute intracerebral hemorrhage. METHOD: Twelve patients presenting with hyperacute, primary ICH undergoing CT scanning and diffusion-perfusion MRI within 6 hours of symptom onset were reviewed. An automated thresholding technique was used to identify decreased apparent diffusion coefficient (ADC) values in the perihematomal regions. Perfusion maps were examined for regions of relative hypo- or hyperperfusion. RESULTS: Median baseline NIH Stroke Scale score was 17 (range, 6 to 28). Median hematoma volume was 13.3 mL (range, 3.0 to 74.8 mL). MRI detected the hematoma in all patients on echo-planar susceptibility-weighted imaging and in all seven patients imaged with gradient echo sequences. In six patients who underwent perfusion imaging, no focal defects were visualized on perfusion maps in tissues adjacent to the hematoma; however, five of six patients demonstrated diffuse ipsilateral hemispheric hypoperfusion. On diffusion imaging, perihematomal regions of decreased ADC values were identified in three of 12 patients. All three subsequently showed clinical and radiologic deterioration. CONCLUSIONS: A rim of perihematomal decreased ADC values was visualized in the hyperacute period in a subset of patients with ICH. The presence of a rim of decreased ADC outside the hematoma correlated with poor clinical outcome. Although perfusion maps did not demonstrate a focal zone of perihematomal decreased blood flow in any patient, most patients had ipsilateral hemispheric hypoperfusion.

Adrenerigic agents. 7.1 Synthesis and beta-adrenergic agonist activity of several 2-pyridylethanolamines.

In a search for new selective bronchodilators, three 2-pyridylethanolamines, i.e., 2-tert-butylamino-1-(5-hydroxy-2-pyridyl)ethanol (2b), a related 6-methylsulfonylmethyl (2c), and, a 6-methyl (2d) derivative, were prepared. These compounds were examined for potential bronchodilator activity in an in vitro test for relaxation of guinea pig tracheal tissue. Potential cardiac stimulant activity was evaluated in vitro by measuring changes in the rate of spontaneously beating guinea pig right atrial muscle. Comparison of potency in the tracheal test relative to that in the atrial procedure provides a measure of selectivity. Results of this study indicate that replacement of the phenyl ring of a para-hydroxylated phenylethanolamine with a 2-pyridyl system generally results in compounds which retain a high order of potency in the tracheal test; however, selectivity for tracheobronchial vs. cardiac tissue is markedly greater for the pyridyl derivatives. The alpha-picoline, 2-tert-butylamino-1-(5-hydroxy-6-methyl-2-pyridyl) ethanol (2d), which bears labile protons at a position meta to the ethanolamine side chain, was about equipotent with the corresponding 6-unsubstituted relative 2b. The reason for the failure of these apparently appropriately located labile protons to enhance beta-adrenoreceptor agonist activity is uncertain.

Adrenergic agents. 6. Synthesis and potential beta-adrenergic agonist activity of some meta-substituted p-hydroxyphenylethanolamines related to salbutamol.

Salbutamol, an adrenergic receptor agonist with selectivity for tracheobronchial vs. cardiac muscle, differs from the catecholamine N-tert-butylnorepinephrine in that it bears a hydroxymethyl, rather than a phenolic, group in the meta position. In a search for new bronchodilating agents with minimal cardiovascular side effects, a series of derivatives, in which this m-hydroxymethyl group is modified, was prepared. These compounds were examined for potential bronchodilator activity in an in vitro test that measures relaxation of guinea pig tracheal smooth muscle. Potential cardiac stimulant activity was evaluated in vitro by monitoring changes in the rate of contraction of spontaneously beating guinea pig right atria. Although many of these compounds retained a high degree of potency, all were less effective than salbutamol in the tracheal test. Several of the derivatives, notably ones bearing 1-hydroxyethyl (1d), 1,2-dihydroxyethyl (1f), 1-hydroxy-2-methoxyethyl (1g), and 2-hydroxy-1-methoxyethyl (1h) substituents in place of the parent's m-hydroxymethyl group, however, were considerably more selective for tracheobronchial vs. cardiac muscle in the in vitro tests utilizing guinea pig tracheal and right atrial muscle.

Adrenergic agents. 8.1 Synthesis and beta-adrenergic agonist activity of some 3-tert-butylamino-2-(substituted phenyl)-1-propanols.

Replacement of the benzylic hydroxyl group of N-tert-butylnorepinephrine with a hydroxymethyl substituent affords a propanolamine homologue which retains a high degree of beta-adrenergic agonist activity. As modification of the meta substituent of catecholic ethanolamines, such as N-tert-butylnorepinephrine, often provides compounds that exert a more pronounced effect in relaxing tracheobronchial smooth muscle (beta2-adrenergic agonist) than in stimulating cardiac muscle (beta1-adrenergic response), a series of 3-tert-butylamino-2-(3-substituted 4-hydroxyphenyl)-1-propanols was prepared. The 3-meta substituents included HOCH2 (1b), H2NCONH (1c), MeSO2NH (1d), H (le), and NH2 (1f). These phenylpropanolamine derivatives were compared with their phenylethanolamine counterparts in in vitro tests that measure the ability of these compounds to relax spontaneously contracted guinea pig tracheal smooth muscle (a measure of potential bronchodilating activity) and to increase the rate of contraction of a spontaneously beating guinea pig right atrial preparation (an indicator of potential cardiac stimulating activity). In these tests all of the propanolamine derivatives included in the study were less potent than their ethanolamine relatives. In both series replacement of the catecholic m-hydroxyl group with the indicated substituents usually resulted in compounds with increased selectivity for tracheobronchial vs. cardiac muscle.

Multisubstrate inhibitors of dopamine beta-hydroxylase. 1. Some 1-phenyl and 1-phenyl-bridged derivatives of imidazole-2-thione.

The synthesis and characterization of some 1-(phenylalkyl)imidazole-2-thiones as a novel class of "multisubstrate" inhibitors of dopamine beta-hydroxylase (DBH) are described. These inhibitors incorporate structural features that resemble both tyramine and oxygen substrates, and as evidenced by steady-state kinetics, they appear to bind both the phenethylamine binding site and the active site copper atom(s) in DBH. A series of structural congeners that incorporate different bridging chain lengths between the phenyl ring (dopamine mimic) and the imidazole-2-thione group (oxygen mimic) define the optimum distance for inhibitory potency and the likely intersite distance in the DBH active site. Additional bridging analogues were prepared to determine the active site bulk tolerance and the effects of heteroatom replacement.

Orally active and potent inhibitors of gamma-aminobutyric acid uptake.

3-Pyrrolidineacetic acid (1a), certain piperidinecarboxylic acids--i.e., 3-piperidinecarboxylic acid (2a), 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (3a), and cis-4-hydroxy-3-piperidinecarboxylic acid (4a)--cis-3-aminocyclohexanecarboxylic acid (5a, cis-3-ACHC), and gamma-aminobutyric acid (6a, GABA) itself are among the most potent inhibitors of [3H]GABA uptake by neurons and glia in vitro. These hydrophilic amino acids, however, do not readily enter the central nervous system in pharmacologically significant amounts following peripheral administration. We now report that N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (2b) is a specific GABA-uptake inhibitor that is more potent, more lipophilic and, in limited testing, as selective as 2a. Similar results were obtained with the N-(4,4-diphenyl-3-butenyl) derivatives of 1a, 3a, and 4a. By contrast, N-(4,4-diphenyl-3-butenyl) derivatives of 5a and 6a were not more potent than the parent amino acids and appear to inhibit GABA uptake, at least in part, by a nonselective mechanism of action. The N-(4,4-diphenyl-3-butenyl)amino acids 1b-4b exhibit anticonvulsant activity in rodents following oral or intraperitoneal administration [Yunger, L.M.; et al. J. Pharmacol. Exp. Ther. 1984, 228, 109].

Multisubstrate inhibitors of dopamine beta-hydroxylase. 2. Structure-activity relationships at the phenethylamine binding site.

1-Aralkylimidazole-2-thiones have been shown to be potent multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1). In the present study, a series of 1-benzylimidazole-2-thiones was prepared to explore the effects of substitution in the benzyl ring on the inhibition of DBH. A detailed structure-activity relationship for in vitro activity was discovered and this was shown by a modified Hansch analysis to correlate (r = 0.91) with four key structural features of the benzyl ring: the presence of a hydroxyl at the 4-position, molar refractivity at the 3-, 4-, and 5-positions, inductive effects of the substituents at the 3-, 4-, and 5-positions, and pi-electron density. The affinity (Kis) of eight substituted inhibitors for DBH was shown to correlate (r = 0.75) with the affinity (KD) of comparably substituted tyramines for the ternary DBH-oxygen-tyramine complex. This correlate is used to support the hypothesis that binding of inhibitor to DBH occurs in a fashion that mimics the binding of tyramine substrates. The most potent inhibitors were selected for study in vivo in the spontaneously hypertensive rat model of hypertension. The changes in vascular dopamine and norepinephrine levels that resulted from oral administration of the inhibitors corresponded to the observed reduction in mean arterial blood pressure. A divergence between in vitro potency and in vivo efficacy upon oral dosing was noted and is suggested to result from an in vivo metabolic conjugation of the phenolic group of inhibitor.

Some benzyl-substituted imidazoles, triazoles, tetrazoles, pyridinethiones, and structural relatives as multisubstrate inhibitors of dopamine beta-hydroxylase. 4. Structure-activity relationships at the copper binding site.

Structure-activity relationships (SAR) were determined for novel multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1) by examining the effects upon in vitro inhibitory potencies resulting from structural changes at the copper-binding region of inhibitor. Attempts were made to determine replacement groups for the thione sulfur atom of the prototypical inhibitor 1-(4-hydroxybenzyl)imidazole-2-thione described previously. The synthesis and evaluation of oxygen and nitrogen analogues of the soft thione group demonstrated the sulfur atom to be necessary for optimal activity. An additional series of imidazole-2-thione relatives was prepared in an effort to probe the relationship between the pKa of the ligand group and inhibitory potency. In vitro inhibitory potency was shown not to correlate with ligand pKa over a range of approximately 10 pKa units, and a rationale for this is advanced. Additional ligand modifications were prepared in order to explore bulk tolerance at the enzyme oxygen binding site and to determine the effects of substituting a six-membered ligand group for the five-membered imidazole-2-thione ligand.

Experimental chronic cerebrovascular spasm in the monkey: an assessment of the functional changes in the cerebral arteries and their protection by diltiazem.

The structure and function of cerebral arteries obtained from a monkey model of chronic cerebral vascular spasm 5 days after hemorrhage have been examined. Narrowing of the larger cerebral arteries demonstrated by angiography at all sites of measurement seems to be due primarily to an increased wall rigidity associated with cellular damage, the resultant inflammatory response and large, long-lasting spontaneous increases in muscle tone. Changes in agonist sensitivity were extremely variable. The reduction of contractility of the vessel wall to a mean of 30% of control diminished the consequence of any changes in active tone characteristics. Neurogenic control on the side of the lesion was remarkably depressed. When treated with diltiazem, beginning 1 day before induction of hemorrhage and continuing to the time of sacrifice, arterial diameter was reduced at only 1 of the 6 standard sites of measurement and then by only a small amount. Neurologic effects invariably seen in the untreated monkeys were prevented by diltiazem. Many of the changes in the artery wall, including structural alterations, were diminished by the drug. Abnormal spontaneous myogenic tone was present but was less in the diltiazem-treated group; however, nerve damage and its functional consequences were not prevented. It is concluded that diltiazem, presumably by preventing the accumulation of intracellular calcium within the cell, prevents the initial events in the evolution of chronic cerebrovasospasm or narrowing. This is probably achieved by a diminishing of the direct vasoconstrictor effects and the toxicity of putative spasmogens released from blood clots, nerves and the brain on the vascular smooth muscle, thus interrupting the sequence leading to pathologic change.

Magnetic resonance imaging of craniopharyngioma.

Craniopharyngiomas are common tumors located in the suprasellar region. Contrast enhancement, cyst formation, and calcification are the three characteristic features of craniopharyngiomas on computed tomographic scan. More than 90% of suprasellar craniopharyngiomas exhibit at least two of these three features, thus providing easy radiologic detection. We treated a 41-year-old man in whom a large suprasellar craniopharyngioma producing severe visual loss was not detected by computed tomography but was easily identified with magnetic resonance imaging. Thus, despite high-resolution computed tomographic scan, large suprasellar craniopharyngiomas can be missed. Magnetic resonance imaging may be superior to computed tomography in detecting these tumors.

N-butyl 2-cyanoacrylate embolization of spinal dural arteriovenous fistulae.

BACKGROUND AND PURPOSE: Because they are not well established, we investigated the technical success and recurrence rates of n-butyl 2-cyanoacrylate (NBCA) embolization of spinal dural arteriovenous fistulae (SDAVF), and assessed clinical outcomes. METHODS: We retrospectively studied all patients with SDAVF treated by NBCA embolization at our institution over an 8-year period. Gait and micturition disabilities were analyzed. Follow-up periods averaged 3.1 years (range, 1 month to 8.9 years). RESULTS: NBCA embolization was feasible in 74% (20/27) of patients. Of 20 patients who underwent embolization, initial embolization failure occurred in two (10%) and fistula occurrence in three (15%). All five patients in whom NBCA embolization failed underwent surgery. All patients who underwent embolization had either improved (55%) or unchanged (45%) gait disability at last follow-up. Seventeen (85%) patients had improved (40%) or unchanged (45%) micturition disability, but three (15%) had worsened. Mean Aminoff gait disability grade significantly decreased at last follow-up (2.4 [1.4] average [SD] vs 3.2 [1.4] [P = .0008]). Mean micturition disability grade decreased, but not significantly (1.4 [1.0] vs 1.7 [1.1] [P = .28]). CONCLUSION: NBCA embolization of SDAVF was technically feasible in 75% of patients. Initial apparent successful embolization was achieved in 90%; the fistula recurrence rate (failure to occlude the draining vein) for NBCA was 15%. Comparing favorably to surgical series, NBCA embolization of SDAVF appears efficacious, significantly improving mean gait disability by almost one grade at last follow-up. Close clinical and angiographic surveillance is mandatory. Longer and more uniform follow-up is needed to determine if clinical improvement and stabilization after NBCA embolization are sustained.

Intraoperative digital subtraction neuroangiography: a diagnostic and therapeutic tool.

We report our experience with intraoperative digital subtraction neuroangiography to demonstrate its application as a diagnostic and therapeutic technique. Intraoperative neuroangiography was performed on 53 occasions in 43 patients using a portable imaging system. Thirty-two procedures were performed for diagnostic purposes after resection of arteriovenous malformations, clipping of aneurysms, or carotid endarterectomy. Unexpected problems were disclosed in seven cases and were surgically remedied immediately in four. In addition, angiography was used as a therapeutic tool in 21 cases to facilitate intraoperative embolization of a vascular lesion or to enable the angioplasty of a vessel inaccessible without direct surgical exposure. We found that by allowing a combined interventional neuroangiographic and neurosurgical approach, intraoperative angiography opened new avenues for treatment of intracranial vascular abnormalities.

Subdural empyema--importance of early diagnosis.

Because subdural empyema (SDE) is an unusual central nervous system infection, recognition is not always prompt. Consequently delays can allow a serious but curable infection to become irreparably damaging or even fatal. This condition, particularly in the early stages, is relatively easy to treat. Personal experience with six patients during the past 3 years promoted us to review the data from UCLA and its affiliated hospitals. Among the 23 cases of SDE reviewed, the predisposing factor in 16 was sinusitis, mastoiditis, or otitis media. The clinical presentation, encompassing a systemic febrile illness, headache, and neurological deficit, was monotonously uniform. The high incidence of paranasal sinus involvement in the adult, middle ear infections in infants, and seizures in 15 patients comprised further clinical clues suggesting the diagnosis. Although usually diagnosed as an intracranial inflammatory process, an initial failure to suspect a purulent collection in the subdural compartment was typical. Although the findings of definitive diagnostic studies (computed tomography or angiography) are strikingly positive in advanced cases, in the earlier stages of this disorder they may be subtly abnormal. Because the mortality and morbidity rates, in some measure, depend on the stage at which the process is arrested, the real challenge lies in making a prompt diagnosis. The most favorable results are associated with early, decisive surgical treatment.

Endoscopic resection of colloid cysts: surgical considerations using the rigid endoscope.

OBJECTIVE: Colloid cysts of the third and lateral ventricles have traditionally been treated by transfrontal and transcallosal microsurgical resection or by stereotactic aspiration. Recently, rigid and flexible ventricular endoscopic techniques have been used to treat these lesions. Our study was undertaken to examine the efficacy of rigid endoscopy in the resection of colloid cysts. METHODS: Fifteen patients with a radiological diagnosis of colloid cysts were given the option of undergoing either endoscopic surgery or craniotomy. The average tumor size was 1.43 cm. Fourteen patients underwent planned endoscopic resections, and a craniotomy was performed initially in one patient. RESULTS: Entire tumor resection was achieved with the endoscope in 12 patients (86%). A craniotomy was required for two colloid cysts that could not be resected endoscopically. In total, complete radiographic resections were achieved in 14 patients (93%). There were no permanent complications, although postoperative deficits included short-term memory loss and hemiparesis, each in one patient. CONCLUSION: Rigid endoscopy affords good optical resolution, high magnification, and excellent illumination. Total or near total resection of colloid cysts should be the goal for all patients and can be achieved using the rigid endoscope, with little morbidity, shortened operative time, reduced length of stay, and resolution of symptoms. Although long-term follow-up is needed, we think that endoscopy should be considered as a primary treatment for most patients.

Early treatment with diltiazem reduces delayed cerebral vascular narrowing after subarachnoid hemorrhage.

Using a primate model of subarachnoid hemorrhage, we have demonstrated the ability of diltiazem to reduce delayed, experimental narrowing of cerebral vessels under clinically realistic conditions. Twelve monkeys were treated identically, except that six received oral diltiazem (20 mg/kg t.i.d.) starting 24 hours after a subarachnoid hemorrhage (SAH) and continuing for 5 days. Neurological examination showed that all untreated monkeys were hyperreflexic and hypotonic on the side contralateral to the SAH. Only two of the six of the diltiazem-treated monkeys had a similar deficit. Control angiograms taken before the SAH were compared with those taken 5 days later. The average vessel diameter at six standard sites in monkeys without diltiazem was 61% of control, whereas the average diameter at the same positions in the diltiazem-treated monkeys was 92% of control (P less than 0.01). In each group, the diameter of the most narrowed artery of each monkey was compared with values at the same site before SAH. The average diameter in the untreated group was 22% of control, significantly smaller than the corresponding value from the diltiazem-treated group, which was 68% (P less than 0.005). Delaying diltiazem treatment until 24 hours after hemorrhage still provides some protection, but less than that given by pretreatment with the drug. This suggests that the processes that eventually result in chronic cerebral vascular narrowing are initiated during the 24-hour period immediately after SAH. We propose that there is initially an acute, severe, calcium-dependent contraction of vascular smooth muscle and associated injury to the vessel wall, including its innervation.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial intracranial aneurysms.

The treatment of 13 patients with bacterial intracranial aneurysms is reported. The incidence of bacterial intracranial aneurysms was 4% of all patients admitted with intracranial aneurysms and 3% of all patients admitted with bacterial endocarditis. Each patient had neurological signs or symptoms suggestive of intracranial disease prior to the diagnosis of an aneurysm. Alpha Streptococcus was the most common infecting organism. All patients were treated with specific, high-dose antibiotics, and five patients underwent surgery as well. There were no surgical deaths. Six of eight nonsurgically treated patients died. A review of the literature confirms a high mortality for patients treated with only antibiotics, and a low mortality for elective surgery. The authors conclude that 1) patients with bacterial endocarditis, who develop sudden severe headache, focal neurological signs or symptoms, or seizures, should undergo serial cerebral angiography every 7 to 10 days throughout their hospitalization; 2) if an aneurysm is identified it should be excised whenever possible; and 3) patients with proximal or multiple aneurysms should be considered for surgery.

Thalamostriate artery aneurysm within the third ventricle. Case report.

The authors report the case of a 7-mm saccular aneurysm, located within the third ventricle and arising from the distal portion of a thalamostriate artery. The patient presented with an intraventricular hemorrhage and was treated via a frontotemporal craniotomy with translamina-terminalis approach for resection of the aneurysm. The etiology of the aneurysm was presumed to be idiopathic. Previously only one other third ventricular aneurysm has been reported. An intraventricular aneurysm arising from a perforating artery should therefore be considered as a rare cause of an intraventricular hemorrhage. Potential surgical approaches to third ventricular aneurysms are discussed.

Intravenous nitroglycerin for the treatment of chronic cerebral vasoconstriction in the primate.

A primate model of chronic cerebral vasoconstriction is presented which closely approximates the human experience following subarachnoid hemorrhage. Treatment of the vasoconstriction with intravenous nitroglycerin produces a modest, but statistically significant, increase in the size of the most constricted vessels (11%, p less than 0.02) when compared with a control infusion of normal saline. The significance of these experiments is discussed.

Effect of diltiazem on experimental chronic cerebral vasospasm in the monkey.

The influence of diltiazem on chronic cerebral vasospasm was studied following subarachnoid hemorrhage (SAH) in a primate model. The model mimics the human experience including the production of neurological deficits. Six monkeys were pretreated with diltiazem (25 mg/kg twice daily) for 2 days prior to surgical production of an SAH and for 5 days after the hemorrhage. This group was compared with six untreated monkeys that also sustained an SAH. The mean diameter of cerebral arteries measured at six angiographic sites was 60.6% of the pre-SAH diameter for the untreated group and 99.7% for the diltiazem-treated group. These values are significantly different (p less than 0.0005). There was no neurological deficit in the pretreated animals. The mean diameter of the "most constricted vessel" in each experiment was 22% of the prehemorrhage diameter for the untreated and 84% for the treated group (p less than 0.0005). Arterial pressure was unaffected by the dosage regimen. These experiments with this primate model of chronic cerebral vasospasm demonstrate that vascular narrowing and neurological deficit can be markedly attenuated by diltiazem pretreatment.