Discovery of a novel isoxazoline derivative of prednisolone endowed with a robust anti-inflammatory profile and suitable for topical pulmonary administration.

A novel glucocorticoids series of (GCs), 6α,9α-di-Fluoro 3-substituted C-16,17-isoxazolines was designed, synthesised and their structure-activity relationship was evaluated with glucocorticoid receptor (GR) binding studies together with GR nuclear translocation cell-based assays. This strategy, coupled with in silico modelling analysis, allowed for the identification of Cpd #15, an isoxazoline showing a sub-nanomolar inhibitory potency (IC50=0.84 nM) against TNFα-evoked IL-8 release in primary human airways smooth muscle cells. In Raw264.7 mouse macrophages, Cpd #15 inhibited LPS-induced NO release with a potency (IC50=6 nM)>10-fold higher with respect to Dexamethasone. Upon intratracheal (i.t.) administration, Cpd #15, at 0.1 µmol/kg significantly inhibited and at 1 µmol/kg fully counteracted eosinophilic infiltration in a model of allergen-induced pulmonary inflammation in rats. Moreover, Cpd #15 proved to be suitable for pulmonary topical administration given its sustained lung retention (t1/2=6.5h) and high pulmonary levels (>100-fold higher than plasma levels) upon intratracheal administration in rats. In summary, Cpd #15 displays a pharmacokinetic and pharmacodynamic profile suitable for topical treatment of conditions associated with pulmonary inflammation such as asthma and COPD.

UK-315716/UK-240455. Pfizer.

Pfizer is developing the atropoisomeric quinoxalinediones, UK-315716 and UK-240255, from a series of NMDA/glycine antagonists for the potential treatment of stroke. Both are compounds are undergoing clinical trials. UK-315716 has improved aqueous solubility and in vivo efficacy over UK-240455, and a lower projected clinical dose of 200 mg compared to 500 mg with UK-240455.

Synthesis and SAR of new 5-phenyl-3-ureido-1,5-benzodiazepines as cholecystokinin-B receptor antagonists.

A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.

Cycloalkyl indole-2-carboxylates as useful tools for mapping the "north-eastern" region of the glycine binding site associated with the NMDA receptor.

A novel series of indole-2-carboxylate analogues of GV 150526 (1) in which the terminal phenyl ring belonging to the side chain present in the position C-3 has been replaced with a bridged cycloalkyl group was synthesized and evaluated for its pharmacological profile. Modelling studies on this class of novel glycine antagonist allowed us to identify an asymmetric lipophilic pocket present in the "North-Eastern" region of the pharmacophoric model of the glycine binding site associated to the NMDA receptor. Among the derivatives prepared, 3-[2-(1-adamantylaminocarbonyl)ethenyl]-4,6-dichloroindole-2 -carboxylic acid 6b and 3-[2-(norbornylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-c arboxylic acid 6l were found to be antagonists acting at the strychnine-insensitive glycine binding site, showing nanomolar affinity for the glycine binding site (Ki = 63 and 19 nM, respectively), coupled with high glutamate receptor selectivity (IC50 > 10(-5) M at the NMDA, AMPA, KA binding sites) and high in vivo potency after systemic administration by inhibition of convulsion induced by NMDA in mice.

The effect of unilateral varus rotational osteotomy with or without pelvic osteotomy on the contralateral hip in patients with perinatal static encephalopathy.

Forty-eight patients with perinatal static encephalopathy were treated with unilateral varus rotational femoral osteotomy for hip subluxation. Twenty-one of the 48 also had concomitant pelvic osteotomy. Twenty-seven of the patients were nonambulators. Bilateral soft-tissue releases had been performed previously in 20 patients. At the time of varus rotational osteotomy, the mean age was 8 years, 11 months. The indication for a varus rotational osteotomy was femoral head subluxation or dislocation in all cases. The preoperative center-edge angle ranged from -8 degrees to 18 degrees (mean, 4 degrees), and on the contralateral side, the center-edge angle ranged from 0 degree to 32 degrees (mean, 19 degrees). The center-edge angle on the operative side at follow-up averaged 25 degrees (-10 degrees to 78 degrees), an improvement of 21 degrees, and on the contralateral side averaged 27 degrees (range, 9 degrees-40 degrees), an improvement of 8 degrees. Forty-seven patients have had no subsequent surgery on the contralateral hip. One patient had a varus rotational osteotomy on the contralateral hip 5 years postoperatively; however, this hip was subluxated at the time of the index procedure. Twelve patients have had no surgery at any time on the contralateral side. None of these patients had deterioration of the contralateral hip. Surgery on one hip should not, in itself, be an indication for surgery on the contralateral concentrically reduced hip with adequate abduction in patients with acetabular dysplasia secondary to perinatal static encephalopathy.

Subtalar arthroereisis for the correction of planovalgus foot in children with neuromuscular disorders.

We studied the results of 140 STA-peg arthroereisis procedures performed for the treatment of planovalgus foot deformity in 78 ambulatory children with neuromuscular disease. Patient age at surgery ranged from 2 + 2 to 14 + 11 years, with a mean of 7 + 9 years. Patients were followed up for an average of 4 + 6 years. The ultrahigh-molecular-weight polyethylene (UHMWPE) STA-peg implant is inserted laterally into the subtalar joint such that its stem extends inferiorly into the calcaneus and its collar abuts the inferior surface of the lateral process of the talus, thereby blocking excessive valgus tilt of the calcaneus. All but five patients (nine feet) had concomitant soft-tissue procedures to balance the foot. The talocalcaneal angle and the talar declination angle were measured on lateral radiographs preoperatively, postoperatively, and at the latest follow-up visit. Patients were evaluated for the presence of pain and hindfoot valgus deformity. Satisfactory results were achieved in 135 (96.4%) feet. Results were unsatisfactory in one foot of each of five patients who had bilateral procedures; one was painful, and four developed varus. The STA-peg was removed in these five patients. No infections or adverse tissue reactions to the STA-peg implant were observed. STA-peg arthroereisis, combined with satisfactory muscle-balancing procedures, can predictably achieve control of planovalgus foot deformity in children with neuromuscular disorders and may obviate the need for long-term orthotic wear.

Pemberton osteotomy for the treatment of developmental dysplasia of the hip in older children.

A retrospective analysis was done of the results of the Pemberton osteotomy for the treatment of developmental dysplasia of the hip in 16 hips of 14 children older than 7 years. The average age of the patients at the time of surgery was 11+6 years and the average follow-up was 4+10 years. Eleven hips required one or more surgical procedures concomitant with the Pemberton osteotomy to achieve a concentric and congruous reduction of the hip joint. None of the hips developed avascular necrosis of the acetabular fragment. The center-edge angle improved from a preoperative average of 1 degree to an average of 30 degrees at the most recent follow-up. Correction of acetabular dysplasia was noted in 14 of the 16 hips, as demonstrated by the improvement in the acetabular index, the center-edge angle, and the Severin class. We believe that the Pemberton osteotomy can be a safe and effective procedure for the treatment of developmental dysplasia of the hip in the older child.

Management of lower-extremity deformities in osteogenesis imperfecta with extensible intramedullary rod technique: a 20-year experience.

Twelve patients (seven boys, five girls) who had osteogenesis imperfecta were treated with an extensible-rod system in 21 femurs and 15 tibias. Indications for use of extensible rods were multiple fractures, long-bone deformity prohibiting bracing and ambulation, and significant remaining linear growth. The average patient age at the time of placement of the extensible rods was 6 + 8 years (range, 2 + 4-10 + 10). Six femurs were treated with overlapping Rush rods; Bailey-Dubow rods were used in the remaining femurs and in all tibias. The average length of follow-up was 5 + 9 years (range, 2 + 0-3 + 2). Preoperatively, four of the 12 patients had never walked; postoperatively, all were ambulators with varying levels of assistance. Fourteen complications occurred, 12 of which required operative revision of the extensible rods. The average time between primary extensible rodding and revision was 5 + 1 years. No complications have occurred to date related to the use of overlapping Rush rods. No growth disturbance resulted from the use of the extensible-rod systems.

Intra-articular hip arthrodesis without subtrochanteric osteotomy in adolescents: technique and short-term follow-up.

Twenty-five patients, 11 to 19 years in age, were treated with hip arthrodesis for an incapacitating painful and stiff hip. Clinical diagnoses included avascular necrosis (AVN) associated with slipped capital femoral epiphysis (SCFE) (7 patients), posttraumatic AVN (6), septic arthritis (4), complication of treatment of developmental dysplasia of the hip (DDH) (4), pathologic fracture of femoral neck through bone cyst with resulting AVN (2), Perthes disease (1), and idiopathic chondrolysis (1). Preoperative motion was minimal or absent in 13 patients, limited in 12, and very painful in 23 patients. A two-incision surgical approach was utilized, providing for an intra-articular fusion technique and internal fixation with precise positioning. The surgical technique described avoids any dissection of the hip abductor musculature or a deforming osteotomy of the proximal femur. Twelve complications occurred in 10 patients, 9 of which required additional operative treatment. At an average postoperative follow-up of 6 years, 10 months, the overall activity level was greatly increased over the preoperative activity level secondary to the relief of pain. Hip arthrodesis is the acceptable salvage procedure for the otherwise healthy, active adolescent or young adult with unilateral hip disease characterized by incapacitating pain and/or an unacceptable fixed position.

Substituted indole-2-carboxylates as in vivo potent antagonists acting as the strychnine-insensitive glycine binding site.

A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor.

Pemberton pelvic osteotomy and varus rotational osteotomy in the treatment of acetabular dysplasia in patients who have static encephalopathy.

Forty-four patients (fifty-two hips) who had static encephalopathy and acetabular dysplasia were managed with a Pemberton osteotomy as part of a comprehensive operative approach. Thirty-three patients had quadriplegia and were unable to walk; the remaining eleven patients had diplegia and could walk. The age at the time of the operation ranged from four years and five months to sixteen years and five months, as an open triradiate cartilage is a prerequisite for the Pemberton procedure. Concomitant operative procedures included a varus rotational osteotomy in fifty of the involved hips, a soft-tissue release in thirty-seven hips, and an open reduction in thirteen hips. The mean center-edge angle preoperatively was -11 degrees (range, -80 to 17 degrees), which improved to a mean of 27 degrees (range, 5 to 62 degrees) at the time of the latest follow-up. The mean duration of follow-up was four years (range, two years to eight years and eight months). At the time of writing, none of the hips had redislocated but one hip had subluxated. Eight of the hips had been painful preoperatively, but none of these was painful at the time of the most recent follow-up. One patient who had not had pain in the hip preoperatively had pain at the time of the follow-up evaluation. There were no complications attributable to posterior uncovering of the hip. The age of the patient at the time of the operation had no discernible effect on the result.

Treatment of severe torsional malalignment syndrome.

Over a 7-year period (1984-1991), nine patients (aged 10-18 years) with 13 involved extremities were operatively treated for symptomatic severe torsional malalignment of the lower extremity and associated patellofemoral pathology. Physical examination and analysis of gait revealed severe rotational deformity characterized by excessive femoral anteversion and external tibial torsion. The cosmetic and functional pathologic effect of this torsional malalignment was centered about the knee joint. In all patients, conservative treatment, including therapy for muscle strengthening and nonsteroidal medication, was unsuccessful in alleviating suspected patellofemoral pain. Subsequent definitive operative treatment in all 13 extremities consisted of corrective osteotomies, internally rotating the distal part of the tibia or externally rotating the distal part of the femur or both. Osteotomies were performed as close to the knee joint as possible. No additional soft-tissue procedures were performed directly to affect patellar tracking. All osteotomies healed without complications. At an average follow-up of 2 years + 7 months (range, 18-48 months) overall, patients had an improvement in gait pattern, extremity appearance, and a marked decrease in knee pain.

Pulseless arm in association with totally displaced supracondylar fracture.

Seven children (3-10 years of age) were treated for a type III supracondylar fracture of the humerus. All fractures were reduced and pinned. Closed reduction was performed in four patients; three required open reduction. Before reduction six of the seven patients did not have a distal palpable pulse in the involved forearm. After reduction of the fractures all patients had a pulseless arm and a seemingly viable hand. Doppler pulses were absent or greatly diminished compared with the normal side in all involved extremities. Six patients underwent immediate antecubital fossa exploration of the brachial artery without arteriogram; one patient, referred to us from another facility, underwent angiography followed by immediate exploration. In three patients the brachial artery was directly damaged or transected and was repaired via saphenous vein graft, with reestablishment of distal pulses in each case. In the other four patients the brachial artery was kinked or entrapped at the fracture site, necessitating microdissection to mobilize the vessel and reestablish pulses in each case. At an average follow-up of 30 months, all seven patients had normal circulatory status, including a radial pulse. All fractures had healed, and all extremities had a normal carrying angle and normal elbow motion. Immediate exploration of the antecubital fossa should be considered if an extremity remains pulseless (to palpation and Doppler) after reduction and stabilization of significantly displaced supracondylar fractures of the humerus.

The acetabular response to proximal femoral varus rotational osteotomy. Results after failure of post-reduction abduction splinting in patients who had congenital dislocation of the hip.

The acetabular response to proximal femoral varus rotational osteotomy was studied radiographically in twenty-eight patients who had had thirty-three congenitally dislocated hips. All of the patients had previously been managed with open or closed reduction followed by use of a spica cast and had worn an abduction orthosis for at least one year after the reduction. The indications for the femoral osteotomy were a persistently increased acetabular index or subluxation, or both. The average of the patients at the time of the femoral osteotomy was twenty-five months. The average preoperative acetabular index was 32 degrees. At an average of seven years after the osteotomy, the acetabular index had improved to an average of 16 degrees. Four hips had had one subsequent procedure for persistent acetabular dysplasia. Despite a failure of the acetabulum to respond to use of an abduction splint, the proximal femoral varus rotational osteotomy stimulated improvement in the acetabular index to within normal limits in twenty-nine of the thirty-three hips.

Legg-Perthes disease in children under 6 years old.

A roentgenographic review was made of 109 patients with unilateral Legg-Perthes disease, all of whom had experienced onset of symptoms prior to their sixth birthday. Roentgenograms taken at the time of healing and at final follow-up were grouped according to Catterall classification and modified Mose rating. The parameters measured were epiphyseal index, center-edge angle, extrusion index, epiphyseal quotient, and center-edge quotient. Average age at final follow-up was 12 years. A change in Mose rating between assessments at healing and final follow-up occurred in 16% of patients, with most of them showing improvement, supporting the concept that femoral heads in young children have the capacity to remodel. However, 24% of patients with Catterall III and IV disease had a poor result at final follow-up. Despite early onset of Legg-Perthes disease, patients with involvement of greater than half the femoral head are at risk for poor roentgenographic result.

Congenital pseudarthrosis.

Five cases of congenital pseudarthrosis of the clavicle were treated with open reduction and fixation with appropriate-sized contoured plates and screws. Iliac bone grafts were used to bridge the gap in four patients; local bone graft was used in the fifth patient. Consolidation was noted an average of 3 months postoperatively in all five cases. The plate and screws were removed in all patients at an average of 16 months postoperatively. Average length of follow-up for the five patients is 4 years. Roentgenograms demonstrate that the clavicle has continued to grow normally. All five patients have pain-free full range of motion and are engaged in unrestricted activities.

Elevation of the medical plateau of the tibia in the treatment of Blount disease.

Seven children, between ten and thirteen years old, had elevation of the medial plateau of the tibia for correction of severe varus deformity secondary to Blount disease. The deformity was severe (grade V or VI according to the system of Langenskiöld and Riska) in all patients; the average preoperative varus deformity, determined by the angle formed by the femoral shaft and the tibial shaft, was 25 degrees. The goal of the operation was restoration of a more normal configuration of the articular surface of the proximal end of the tibia. This was accomplished by direct elevation of the depressed medial tibial plateau. All patients had an osteotomy to correct the alignment of the tibia. The osteotomy was performed concomitant with the elevation of the plateau in three patients, before the elevation in three, and after the elevation in one patient. Four patients had a concomitant osteotomy of the femur to align the knee joint parallel to the floor. The results were good in five patients and fair in two.

Fractures after Wagner limb lengthening.

A retrospective review of our experience with fractures after 27 Wagner limb lengthenings (23 patients) was undertaken. Ten fractures occurred after lengthening in eight patients (six spontaneous, four traumatic). Seven patients fractured despite a "staged" removal of the fixation plate. Seven of 10 fracture patients required open reduction/internal fixation (ORIF) to obtain union and/or satisfactory alignment. Our results indicate that patients with a congenital limb length inequality are prone to spontaneous fracture after Wagner limb lengthening. These results raise serious questions regarding the quality of bone healing after a Wagner-type lengthening for congenital limb length inequality.

Premature closure of the triradiate cartilage: a potential complication of pericapsular acetabuloplasty.

A case of premature triradiate cartilage closure secondary to a Gill acetabuloplasty performed at age 14 months is reported. The deficiency in acetabular development and failure of the pelvis to grow to its anticipated height is documented. A proximal femoral redirectional osteotomy and an innominate osteotomy performed near maturity improved femoral head coverage and hip biomechanics. Acetabuloplasties performed adjacent to the triradiate cartilage typically do not have any adverse effect on its function. Despite this low risk of injury to the triradiate cartilage after a Gill or Pemberton acetabuloplasty, long-term follow-up is recommended to observe acetabular development. Premature closure is most likely to occur if the bone graft used to maintain fragment displacement crosses the triradiate cartilage.

Sagittal plane analysis in idiopathic scoliosis patients treated with Cotrel-Dubousset instrumentation.

One hundred sixty patients with idiopathic scoliosis underwent preoperative and postoperative sagittal plane analysis of the thoracic spine, thoracolumbar junction, and lumbar spine. The data suggest that mild to moderate improvements in thoracic hypokyphosis are possible. When crossing the thoracolumbar junction, reversal of rod bend and reversal of hooks on the derotation rod appears to provide the most physiologic sagittal contour. Cotrel-Dubousset instrumentation to the mid and distal lumbar spine can preserve and, at times, enhance lumbar lordosis.