Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1.

BACKGROUND AND PURPOSE: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M(1) mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. EXPERIMENTAL APPROACH: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. KEY RESULTS: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. CONCLUSIONS AND IMPLICATIONS: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.

Metastatic tumors of the sella turcica masquerading as primary pituitary tumors.

Tumors metastatic to the pituitary gland are uncommon, but may mimic a typical pituitary adenoma and are an important part of the differential diagnosis of sellar mass lesions. Pituitary metastases were treated by transsphenoidal microsurgical removal in 14 patients. Most tumors appeared in men in the sixth and seventh decades of life. Half of the patients presented with visual loss, 6 had anterior hypopituitarism, and 4 had diabetes insipidus. Primary cancer had been diagnosed and treated previously in 5 patients. In the remaining 9 patients, the transsphenoidal operation provided the initial diagnosis of cancer, and primary lesions subsequently were detected in all but 2. Transsphenoidal surgery also provided satisfactory decompression of the mass effect related to the tumors, improving the presenting symptoms in the majority of patients, and the surgery was free of mortality or serious complications.

Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and CNS penetration in the rat.

A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.

Predictors of hospital mortality in older patients with subdural hematoma.

OBJECTIVE: To identify presenting characteristics of older patients with subdural hematoma who are unlikely to survive hospitalization. DESIGN: A retrospective cohort. PATIENTS: All patients > or = 65 years of age hospitalized at a tertiary care center from 1985-1990 with the primary diagnosis of subdural hematoma. MEASUREMENTS: Chart review was performed to characterize presenting clinical characteristics, hospital course, and outcome at the time of hospital discharge. MAIN RESULTS: Of the 157 eligible patients, 42% (66/157) were > or = 80 years of age. Although 30% of patients had no recorded trauma, 54% experienced a fall before hospitalization. Twenty-six percent (47/157) of patients had been on antithrombotic therapy (14 on coumadin, two on heparin, 31 on antiplatelet agents, one on both coumadin and an antiplatelet agent). Sixty percent of patients had no focal neurologic findings, and the mean Glasgow Coma Score was 12.3 (+/- 3.6). The hematoma was considered chronic in 49% (77/157) of cases, based on time from antecedent trauma or on neuroimaging criteria. Midline shift by neuroimaging was present in 69%. Overall hospital mortality was 31% (48/157). Using logistic regression to control for other factors, level of consciousness (Glasgow Coma Score < = 7) (OR = 10.4), age > or = 80 (OR = 3.7), duration of hematoma considered acute (OR = 2.7), and craniotomy (OR = 2.6) were significantly associated with hospital mortality. Presence of focal symptoms, previous antithrombotic medication use, nature of trauma, comorbidity score, and presence of midline shift were not associated with hospital mortality. CONCLUSIONS: Among older patients with subdural hematoma, level of consciousness, extreme old age, duration of the hematoma, and nature of the intervention were significantly associated with hospital mortality. These factors should help physicians in clinical decision making and formulation of advance directives for geriatric patients with subdural hematoma.

A simple test phantom for stereotactic computed tomography.

An easy-to-use phantom has been constructed for checking the accuracy of a stereotactic computed tomography localization system. This phantom has been used on a commercially available stereotactic radiosurgery system. With this system, the phantom reference point, whose location is established by means of a precision measuring implement, can be localized by a computed tomography (CT) scanner with a standard deviation of measurement that is less than 0.3 mm in three orthogonal axes.

False aneurysm complicating carotid endarterectomy.

We present two cases of false aneurysm after carotid endarterectomy with primary arteriotomy closure. In both cases, infection appeared to be the precipitating cause. Both lesions were repaired with a saphenous vein patch graft, but infection in one patient persisted, and recurrence of a false aneurysm required ligation of the common carotid artery. There were no neurological sequelae in either patient. A review of the English language literature, our experience, and personal communications yielded 57 cases of false aneurysm. The overall incidence of false aneurysm after carotid endarterectomy was 0.30%. There was no significant difference in the incidence after endarterectomy alone and that after endarterectomy and patch grafting. A significant increase in neurological deficit occurred only when carotid ligation was used, with a morbidity/mortality of 50% in eight reported cases. Infection was the major cause of false aneurysm after endarterectomy; it occurred in 50% of cases closed primarily without patch grafting. Repair with a saphenous vein patch graft and monofilament synthetic suture, plus liberal use of antibiotics, should be considered in the treatment of this condition.

Post-traumatic acalculous cholecystitis on a neurosurgical service.

Post-traumatic acalculous cholecystitis is a potentially lethal complication that may develop in patients during hospitalization for trauma. Three case reports illustrate that obscuration of many early diagnostic symptoms and signs may make this complication particularly treacherous in the neurosurgical patient. Suspicion should be aroused by unexplained fever, leukocytosis, elevated serum bilirubin and alkaline phosphatase values, and developing intolerance to oral or tube feedings. There may be a rapid progression to signs of an acute abdominal condition. Symptoms are most likely to occur 1 week to 1 month after the episode of trauma. Patients of all ages are susceptible. Diagnosis is best confirmed by noninvasive iminodiacetic acid hepatobiliary scanning accompanied by ultrasound or abdominal computed tomographic scanning. The treatment of choice is emergency cholecystectomy. The cause is most likely multifactorial and is probably related to hypotension, sepsis, or biliary stasis with subsequent cystic duct obstruction. Although this disease is rare, its incidence is apparently increasing, and a high index of suspicion is warranted in the neurosurgeon involved in the care of the biliary tract disorder.

Left atrial myxoma with cerebral emboli.

Infarction of the central nervous system secondary to embolism from left atrial myxoma is a recognized phenomenon. However, myxoma as the source of an embolus may be overlooked if an index of suspicion is not present during the evaluation of the patient with a stroke without a known cause. We present a case report that illustrates some of the pitfalls and characteristic findings present in the evaluation of these patients. The magnetic resonance image of multiple cerebral aneurysms and infarction associated with this condition is presented along with a unique, arteriographically proven resolution of a fusiform cerebral aneurysm after the removal of the cardiac tumor. A review of published case reports suggests that, if the cardiac tumor is recognized and treated quickly, the ultimate prognosis, while uncertain, is usually good. However, because the potential exists for recurrence of the cardiac tumor, for enlargement of the cerebral lesions, or for late development of cerebral lesions, long term follow-up is mandatory and a vigorous work-up must be pursued if the patient again becomes symptomatic or develops central nervous system manifestations for the first time.

Fixation of fractures of the lower cervical spine using methylmethacrylate and wire: technique and results in 99 patients.

Surgical stabilization of traumatic fracture-dislocations of the lower cervical spine with wire and methylmethacrylate remains a controversial procedure. Yet, the resultant immediate fixation with minimal patient morbidity seems to indicate that this method provides an ideal stabilization construct. We describe and report the outcome of a technique of posterior cervical fixation with methylmethacrylate and wire for stabilization of traumatic fractures of the lower cervical spine. Over a 12-year period, 124 fracture-dislocations of the lower cervical spine in 99 patients (mean age, 32 years; range, 15-76 years) were treated at this institution using a posterior methylmethacrylate and wire technique. Eighty-two patients had a posterior element fracture; 28 had a vertebral compression with posterior ligamentous injury; and 14 had a ligamentous injury alone. Thirty-six patients were neurologically intact upon admission, while the rest had radiculopathy or partial or complete myelopathy. Ninety-one patients were available for follow-up [mean, 18.6 months; range, 1-100 months (8.33 years)]. Eighty-eight patients (97%) had a stable fixation and 77 (85%) had resumed preoperative activity or were working but with a residual deficit. Complications included fixation failure requiring a second operation in 3 patients, nonlethal pulmonary embolism in 2 patients, lethal pulmonary embolism in 1 patient, and a superficial wound infection in 3 patients (none affected the underlying fixation construct). These results indicate that this technique is a safe, simple, and effective method for stabilizing the lower cervical spine that allows rapid patient mobility with minimal morbidity.

Revision of anterior cervical pseudoarthrosis with anterior allograft fusion and plating.

Anterior cervical discectomy and fusion is an efficacious procedure used to treat a variety of cervical spinal disorders, including spondylosis, myelopathy, herniated discs, trauma, and degenerative disc disease. Pseudarthrosis, or failure of fusion, may be the most common complication of spinal fusion procedures. Nineteen consecutive patients with symptomatic pseudarthrosis following failed anterior cervical fusions were treated with anterior cervical revision using iliac crest allografts and either the Cervical Spine Locking Plate system (10 patients) or the Trapezial Osteosynthetic Plate system (nine patients). The mean age of the nine men and 10 women undergoing treatment was 49.1 years (range 25-72 years). Eleven patients (57.9%) exhibited pseudarthrosis at one level, six (31.5%) at two levels, and two (10.5%) at three levels. The indications for revision were intractable neck pain with radiculopathy (17 patients) or myelopathy (two patients), with evidence of pseudarthrosis on plain cervical radiography as well as computerized tomography (CT) or single-photon emission computerized tomography (SPECT) scanning, or both. All eight patients evaluated with SPECT showed increased focal uptake consistent with pseudarthrosis, which was subsequently confirmed intraoperatively in all eight. The average follow-up period was 22.4 months (range 12-42 months). Solid osseous fusion was achieved over all 28 levels in all 18 patients available for follow-up review (100%). One patient died 4 months postoperatively from myocardial infarction related to preexisting coronary artery disease. There were no intraoperative complications; postoperatively, two patients (10.5%) experienced transient hoarseness. Anterior revision of failed cervical fusions using allograft interbody fusion material and anterior plating is a safe and efficacious procedure. In this series, the use of allografts avoided donor site morbidity without adversely affecting fusion rates. Rigid internal fixation was achieved by means of anterior plating without increasing surgical morbidity rates. The SPECT imaging technique has the potential to reliably confirm the diagnosis of pseudarthrosis.

A clinical comparison of one- and two-screw odontoid fixation.

OBJECT: The optimal treatment of Type II odontoid fractures is controversial. Various therapies have been used, including nonrigid immobilization, halo orthosis, posterior atlantoaxial arthrodesis, and odontoid screw fixation. Of these, odontoid screw fixation is the only treatment modality that provides immediate stabilization and preserves normal motion at C1-2. It has been suggested in cadaveric biomechanical studies that there is no advantage to using more than one screw for anterior odontoid fixation. The authors compared the clinical safety and efficacy of one- and two-screw anterior odontoid fixation. METHODS: The authors retrospectively reviewed the medical records and radiographs of 42 consecutive patients who had undergone fixation for treatment of odontoid fractures at a single institution between 1989 and 1995. The group treated with a single screw consisted of 20 patients (11 males and nine females) with an average age of 54 years. The union rate in this group, as determined by postoperative dynamic radiographs, was 81%. The group treated with two screws consisted of 22 patients (13 men and nine women) with an average age of 64 years, whose union rate was 85%. CONCLUSIONS: Anterior odontoid screw fixation is a safe and efficacious treatment for odontoid fractures. In the authors' experience there was no significant difference in the successful union rates achieved with either the one- or two-screw fixation techniques (81% and 85%, respectively; chi(2) = 0.09, p = 0.76).

Aneurysmal bone cyst with fibrous dysplasia of the parietal bone. Report of two cases.

The diagnostic and surgical aspects of aneurysmal bone cysts contiguous to fibrous dysplasia of the parietal bone are reported in two adolescents. While aneurysmal bone cyst and fibrous dysplasia are known to be associated, the association is rare and has not been reported previously in the calvaria.

Arteriovenous fistula as a complication of C1-2 transarticular screw fixation. Case report and review of the literature.

A case is reported of a vertebral artery-to-epidural venous plexus fistula as a complication of posterior atlantoaxial facet screw fixation. The use of transarticular screws to stabilize the C1-2 joint has become an increasingly popular fixation technique, most notably for atlantoaxial instability due to trauma or rheumatoid disease. Despite the fact that this approach is technically challenging, there have been few reports of complications associated with C1-2 transarticular fixation. Although damage to the vertebral artery is a documented hazard of transarticular fixation at this level, a symptomatic arteriovenous fistula resulting from the procedure has not been described previously. The etiology, presentation, and treatment of this unusual complication are discussed.

Synthesis and biological properties of some 3-[(N-substituted-amino)pyridinium-4-thiomethyl]-7-[2-(2-amino-thiazol- 4-yl)-2-(Z)-(methoxyimino)acetamido]ceph-3-em-4-carboxylates.

The synthesis and antibacterial activity of a series of beta-lactamase stable, broad spectrum 7-[2-(2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-cephalo sporins, characterised by a C-3-[N-(substituted-amino)pyridinium-4-thiomethyl] group, is described. Gram-positive and Gram-negative bacteria including extended spectrum beta-lactamase-producing strains were most susceptible to the N-amino- and N-methylamino derivatives (3a) and (3b); with the exception of Pseudomonas aeruginosa, (3b) was more active in vitro and in vivo than cefpirome or ceftazidime.

Structure-activity relationships within a series of C(7)-substitutedoxyiminocephalosporins containing the C(3)-methylaminopyridiniumthiomethyl substituent. Synthesis and biological properties of BRL 57342 and some close analogues.

(6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-[(Z)-[(S)-carboxy(3,4- dihydroxyphenyl)methyl]oxyimino]acetamido]-3-(1-methylaminopyri dinium-4-thiomethyl)ceph-3-em-4-carboxylate sodium salt (BRL 57342, 1f) combines excellent in vitro antibacterial potency against Gram-positive and Gram-negative bacteria, including P. aeruginosa and Acinetobacter spp., with excellent stability to extended spectrum beta-lactamases. This potency is reflected in in vivo efficacy studies.

Studies on semi-synthetic 7 alpha-formamidocephalosporins. III. Synthesis and antibacterial activity of some 7 beta-[D-2-(aryl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl amino] acetamido]-7 alpha-formamidoceph-3-em-4-carboxylate derivatives.

The synthesis and antibacterial activity of 7 beta-[D-2-(aryl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl) carbonylamino] acetamido]-7 alpha-formamidocephalosporins with various substituents at the C-3 position of the cephalosporin nucleus is described. Inhibition of Gram-positive and Gram-negative bacteria including beta-lactamase producing strains was observed with phenyl as the aryl residue. The 3,4-dihydroxyphenyl group further enhanced the activity against Gram-negative organisms; in this series, the 3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl] and 3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl] analogues (2 and 12b) exhibited exceptional activity against Gram-negative bacteria, including Pseudomonas aeruginosa.

Synthesis and biological activity of 3-(N-substituted pyridinium-4-thiomethyl)-7 alpha-formamido cephalosporins.

The synthesis and antibacterial activity of a series of 3-(1-substituted pyridinium-4-thiomethyl)-7 alpha-formamido cephalosporins is described. All the derivatives showed good potency and stability to bacterial beta-lactamases. The antibacterial efficacy seen with the N-alkyl pyridinium substituents was enhanced by the introduction of a catecholic side chain at C-7 and by preparation of N-(substituted amino)pyridinium derivatives.

Novel C-2 substituted carbapenem derivatives. Part IV. Synthesis and biological activity of five membered heteroaromatic derivatives.

The synthesis, antibacterial activity, and stability to human dehydropeptidase-1 (DHP-1) of a novel series of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-heterocyclylcarbapen-2-em-3-carb oxylates are described. Of the compounds investigated 1,5-disubstituted pyrazol-3-yl and 3-substituted isoxazol-5-yl derivatives have the best combination of antibacterial activity and stability to DHP-1. They are particularly active against community-acquired respiratory tract pathogens and have stabilities to DHP-1 superior to that of meropenem.

Posterior lumbar interbody fusion with the keystone graft: technique and results.

The technique of posterior lumbar interbody fusion reported here consists of the following steps: The confluence of the spinous process and lamina removed en bloc during the exposure is contoured into three keystone plugs; the anterior third of the disc space is packed with bone fragments; the keystone plugs are tapped in posterior to the bone fragments and locked into place; and excess bone fragments are laid over the facets bilaterally and over the transverse processes if necessary to fuse the facet joints and create a posterior fusion. This fusion technique precludes the need for banked bone or for the harvest of autogenous iliac bone, and provides posterior stability with the facet fusion despite the removal of the posterior elements. This technique has been used in 172 patients, with excellent or good results in 129 patients (75%); included in that number were 82 patients expecting compensation and 25 patients with failed-back syndrome.

Surgical repair of aneurysms of the posterior inferior cerebellar artery--a clinical series.

Aneurysms of the posterior inferior cerebellar artery are relatively rare. Fourteen such aneurysms (10 vertebral, 4 peripheral) are reported, and their clinical presentation, surgical therapy, and outcome are discussed. All 14 patients had suffered a subarachnoid hemorrhage; 93% (n = 13) underwent direct clipping of the aneurysm while 7% (n = 1) underwent coating of the aneurysm. Two patients died in the perioperative period (one from vasospasm and one from rebleeding). Full activity was achieved by all but one (92%) of the remaining patients in extended follow-up.