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Biomedical subjects

C L Branch

Publications and source records attributed to C L Branch.

At least 19 recordsLinked to original sources
PubMed2001

Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor.

Starting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19, which has high affinity for the dopamine D3 receptor (pKi 8.3) and > or = 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%, t1/2 5.2h).

Animals↗
PubMed2001

Predictors of successful extubation in neurosurgical patients.

A respiratory therapist-driven weaning protocol incorporating daily screens, spontaneous breathing trials (SBT), and prompts to caregivers has been associated with superior outcomes in mechanically ventilated medical patients. To determine the effectiveness of this approach in neurosurgical (NSY) patients, we conducted a randomized controlled trial involving 100 patients over a 14-mo period. All had daily screens of weaning parameters. If these were passed, a 2-h SBT was performed in the Intervention group. Study physicians communicated positive SBT results, and the decision to extubate was made by the primary NSY team. Patients in the Intervention (n = 49) and Control (n = 51) groups had similar demographic characteristics, illness severity, and neurologic injuries. Among all patients, 87 (45 in the Control and 42 in the Intervention group) passed at least one daily screen. Forty (82%) patients in the Intervention group passed SBT, but a median of 2 d passed before attempted extubation, primarily because of concerns about the patient's sensorium (84%). Of 167 successful SBT, 126 (75%) did not lead to attempted extubation on the same day. The median time of mechanical ventilation was 6 d in both study groups, and there were no differences in outcomes. Overall complications included death (36%), reintubation (16%), and pneumonia (9%). Tracheostomies were created in 29% of patients. Multivariate analysis showed that Glasgow Coma Scale (GCS) score (p < 0.0001) and partial pressure of arterial oxygen/fraction of inspired oxygen ratio (p < 0.0001) were associated with extubation success. The odds of successful extubation increased by 39% with each GCS score increment. A GCS score > or = 8 at extubation was associated with success in 75% of cases, versus 33% for a GCS score < 8 (p < 0.0001). Implementation of a weaning protocol based on traditional respiratory physiologic parameters had practical limitations in NSY patients, owing to concerns about neurologic impairment. Whether protocols combining respiratory parameters with neurologic measures lead to superior outcomes in this population requires further investigation.

Adolescent↗
PubMed2000

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.

Animals↗
PubMed2000

Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A.

SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.

Animals↗
PubMed1999

Review of 31 cases of anterior thoracolumbar fixation with the anterior thoracolumbar locking plate system.

Anterior fixation devices for the thoracolumbar spine have gained wide acceptance as viable alternatives to long-segment posterior fixation in cases of thoracolumbar spine trauma. This review was undertaken to evaluate the safety and efficacy of the Synthes anterior thoracolumbar locking plate (ATLP) system. Over a 3-year period, 31 patients with unstable traumatic fractures of the thoracolumbar spine underwent corpectomy, placement of a structural bone graft, and anterior fixation in which the Synthes ATLP system was used. Long-term follow-up data were obtained in 29 patients. Two patients were lost to follow up, one at 4 months and the other at 1 year. In the remaining patients, the average length of follow up was 20 months. In all patients radiographic evidence of solid bone fusion was demonstrated on follow-up plain x-ray films, and there were no signs or symptoms of pseudarthrosis. No patient suffered neurological deterioration as a result of surgery, and there was relatively little morbidity associated with this plating system. To date, none of the patients in this study has developed any delayed complications related to the fixation device. In one patient, who had sustained a severe flexion injury, loosening of the anterior fixation device occurred, and the patient developed progressive kyphosis, which required a posterior stabilization procedure. These results appear slightly better than those obtained in published studies in which other anterior plating systems were used, indicating that this system is safe and effective in the treatment of unstable fractures of the thoracolumbar spine.

Journal Article↗
PubMed1999

Novel 1,2,3,4-tetrahydroisoquinolines with high affinity and selectivity for the dopamine D3 receptor.

Using clearance and brain penetration studies as a screen, tetrahydroisoquinoline 3 was identified as a lead having low clearance in rats (CLb 20 ml/min/kg). Introduction of a 7-CF3SO2O- substituent into the tetrahydroisoquinoline, followed by replacement of the biphenylamido group of 3 by a 3-indolylpropenamido group gave 31, having high D3 receptor affinity (pKi 8.4) and 150 fold selectivity over the D2 receptor.

Animals↗
PubMed1998

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).

Adolescent↗
PubMed1998

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.

Carbapenems↗
PubMed1997

Posterior lumbar interbody fusion in the treatment of symptomatic spinal stenosis.

Lumbar spinal stenosis is often the result of advanced degeneration of motion segments of the lumbar spine. Loss of disc height, facet displacement and hypertrophy, spondylosis, and spondylolisthesis, as well as buckling of the ligamentum flavum and annulus fibrosus, all contribute to impingement on the spinal canal and intervertebral foramen in lumbar stenosis. There is a subgroup of patients with spinal stenosis in whom the spine is unstable preoperatively or becomes destabilized following decompression who would benefit from an initial fusion procedure. Posterior lumbar interbody fusion (PLIF) addresses several aspects of the multifactorial pathophysiology responsible for spinal stenosis and may arrest the degenerative changes at the fused level. Fusion, in particular PLIF, should be considered in complex cases of lumbar spinal stenosis, most notably in patients with postlaminectomy stenosis or stenosis associated with spondylolisthesis.

Journal Article↗
PubMed1997

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.

Adult↗
PubMed1996

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.

Arteriovenous Fistula↗
PubMed1995

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.

Age Factors↗
PubMed1995

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.

Animals↗