WAY-318068: a novel, potent and selective noradrenaline re-uptake inhibitor with activity in rodent models of pain and depression.

BACKGROUND AND PURPOSE: Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity. EXPERIMENTAL APPROACH: In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one). KEY RESULTS: WAY-318068 is a potent and effective inhibitor of the NET with a K(i) of 8.7 nM in a binding assay, and an IC(50) of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits. CONCLUSIONS AND IMPLICATIONS: Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.

Safety of the limited open technique of bone-transfixing threaded-pin placement for external fixation of distal radial fractures: a cadaver study.

OBJECTIVE: To examine the safety of threaded-pin placement for fixation of distal radial fractures using a limited open approach. DESIGN: A cadaver study. METHODS: Four-millimetre Schanz threaded pins were inserted into the radius and 3-mm screw pins into the second metacarpal of 20 cadaver arms. Each threaded pin was inserted in the dorsoradial oblique plane through a limited open, 5- to 10-mm longitudinal incision. Open exploration of the threaded-pin sites was then carried out. OUTCOME MEASURES: Injury to nerves, muscles and tendons and the proximity of these structures to the threaded pins. RESULTS: There were no injuries to the extensor tendons, superficial radial or lateral antebrachial nerves of the forearm, or to the soft tissues overlying the metacarpal. The lateral antebrachial nerve was the closest nerve to the radial pins and a branch of the superficial radial nerve was closest to the metacarpal pins. The superficial radial nerve was not close to the radial pins. CONCLUSION: Limited open threaded-pin fixation of distal radial fractures in the dorsolateral plane appears to be safe.

A modification of Henry's anterior approach to the humerus.

A retrospective chart review identified patients who had surgery through Henry's standard anterior and anterolateral approaches to the humerus. Of the patients contacted, 62% had problems with the skin incision with reports of pain, numbness, and tingling around the scar. The frequency of cutaneous problems including neuroma prompted an anatomic study; the lower lateral cutaneous nerve branches to the arm were dissected in seven cadaver arms to determine their course. Henry's incision was then compared with a midline anterior incision. The cutaneous nerves were noticeably less numerous and smaller in diameter in the midline incision, probably related to the internervous, or watershed zone of cutaneous nerves in the anterior midline of the arm. Henry's standard intermuscular humeral exposure was no more difficult with the anterior midline incision. This study supports the notion that an anterior midline incision to approach the shaft of the humerus would minimize scar discomfort from cutaneous nerve injury.

The carpal stretch test.

OBJECTIVE: To compare the sensitivity of traditional motion studies, bone scintigraphy and radiocarpal arthrography to a "carpal stretch test," for evaluation of dynamic dissociative carpal instability. DESIGN: Experimental study comparing the results of the tests to the findings of arthroscopy, the "gold standard." SETTING: A university hospital-based upper extremity practice. PATIENTS: Six patients with chronic wrist pain, arthroscopically confirmed proximal row ligamentous disruption and radiographs not suggestive of proximal row instability. INTERVENTIONS: The carpal stretch test: both affected and unaffected wrists were subjected to the same testing, wherein the wrist was suspended from finger traps for 10 minutes by a 4.5-kg weight. Standardized posteroanterior radiographs were taken of the suspended wrists. MAIN OUTCOME MEASURES: Disruption of Gilula's arcs I and II, and sensitivity of the carpal stretch test compared with other investigations. MAIN RESULTS: Step deformities ranging from 2.5 to 6 mm (average 3.7 mm) were recorded in the affected wrists and 0 to 4 mm (average 1.5 mm) in the "unaffected" wrists. The test was more sensitive than traditional radiography, arthrography and scintigraphy in defining both presence and site of proximal carpal row ligamentous tears and was almost as sensitive as arthroscopy. CONCLUSION: In patients with chronic wrist pain and dynamic dissociative wrist instability, the carpal stretch test may prove to be a valuable screening tool for detecting ligamentous tears of the proximal carpal row.

Accuracy of intraoperative assessment of acetabular prosthesis placement.

Anteversion and vertical tilt of the acetabular prostheses in 50 consecutive total hip arthroplasties were prospectively evaluated during surgery (by the surgeon, using an alignment guide) and radiographically (calculated). From postoperative standardized radiographs vertical tilt was measured directly and anteversion was calculated. The mean error of vertical tilt was 5 degrees (range, 0 degrees - 20 degrees). The mean error of version was 9 degrees (range, 0 degrees - 24 degrees). The reliability of prosthesis placement in a predetermined zone was examined. Although the surgeons believed that all 50 cups were inside this zone, radiographic measurements revealed that 21 of the cups were actually outside. It is concluded that vertical tilt can be reasonably assessed during surgery. Anteversion, however, cannot be accurately assessed during surgery, despite use of the alignment guide.

Harvesting of the sural nerve with a tendon stripper.

The nerve most commonly used for peripheral nerve reconstruction is the sural nerve. The nerve can be dissected free through one long calf incision, by utilizing multiple small incisions, or by using a tendon stripper. We studied 12 above-knee amputation specimens harvesting the nerve in the ways described. We found that the length of nerve harvested averaged 32, 36, and 25 cm for the open, limited open, and stripper techniques, respectively. Epineurial damage occurred with the stripper, but no perineurial damage was documented histologically. We concluded that the closed method (stripper) of harvesting sural nerve would provide quality graft material, but of unpredictable length. When reliably long segments of nerve are required, at least a limited open or an open approach for harvest is recommended.

Radiographic calculation of anteversion in acetabular prostheses.

The position of the acetabular prosthesis is critical for preventing dislocation following total hip arthroplasty. The reliability of a mathematical model for radiographically calculated acetabular cup version was examined. A porous-coated anatomic acetabular prosthesis was mounted in a mold. Anteroposterior radiographs were taken with the cup in five different positions of anteversion. These were reviewed by five orthopaedic surgeons, and measurements were taken from each radiograph. From these measurements, the mathematically derived degree of version was calculated. The results were examined for accuracy and intraobserver reliability. It was concluded that intraobserver reliability was very good and that the accuracy was within a clinically acceptable range. This technique could be useful in studying the "safe zone" for acetabular prostheses.

Computerized tomographic evaluation of acute distal radial fractures.

To learn whether computerized tomography offered additional useful information over conventional radiographic evaluation of acute distal radial fractures in the younger adult, we scanned 22 consecutive injured wrists. Of the distal radial fractures in 19 wrists, sixteen were defined on plain films as intra-articular. In contrast, computerized tomography demonstrated that all fractures of the distal radius had intra-articular extension. In 3 wrists interpreted as being normal on plain films, despite clinical suspicion of a fracture, fractures were confirmed by computerized tomography. As a result of computerized tomography, injuries were assigned a higher Frykman value in 5 cases, and consideration of alternative patient management became necessary in 5 of the 22 patients.

The osteocutaneous fibula flap: an anatomic study.

Recent studies related to the fibula flap have disagreed regarding the anatomy of the cutaneous branches of the peroneal artery. To clarify this issue, various dissections of 35 injected fresh cadaver legs were done. Identifiable skin branches were found in 23 of 25 dissections. Skin branches from the proximal third of the peroneal artery always travelled an intramuscular course. Skin branches from the distal two-thirds of the peroneal artery were usually affixed to the posterior crural septum. Legs with peroneal artery skin branches had from three to seven branches (average: 4.7); each branch contributed to the fibular periosteal blood supply. The most reliably found skin branch was located within 2 cm of the fibula midpoint. These findings reinforce the fact that a large skin island supplied by branches of the peroneal artery can be harvested with the fibula flap, and that the most reliable cutaneous vessels are found in the lower two-thirds of the leg, run posterior to the fibula in the posterior crural septum, and are always associated with muscular side branches.

A new technique of catheter placement for measurement of forearm compartment pressures.

Hitherto described techniques of catheter placement in the forearm for compartment pressure measurement in the evaluation of forearm compartment syndrome place the underlying neurovascular structures at risk for injury. Based on the cross-sectional anatomy of the forearm, two previously undescribed routes are detailed that provide safer access to the deep volar forearm compartment. Via the ulnar approach, the catheter is inserted medial to the subcutaneous border of the ulna and advanced radially, transversely, skimming over the volar aspect of the ulna into the belly of flexor digitorum profundus. Via the dorsal approach the catheter is inserted radial to the subcutaneous border of the ulna in the supinated forearm. Using the ulna as a guide the catheter is advanced through the dorsal forearm compartment and interosseous membrane into the deep volar compartment. By this route, pressures of both dorsal and volar compartments of the forearm can be measured with a single catheter insertion.

The use of coronal computed tomography in the evaluation of Kienbock's disease.

In a prospective study of 12 consecutive patients with Kienbock's disease, direct coronal CT of the wrist was more sensitive than plain films and plain film tomography in demonstrating structural change including sclerosis, compression and fractures of the lunate. Fractures are more common in Kienbock's disease than previously reported. Earlier detection of fractures by CT, before collapse of the lunate occurs, may allow treatment to prevent the collapse.

Rotating shaft avulsion amputations of the thumb.

In a three-year period twenty-nine patients were treated for rotating shaft avulsion amputations of the thumb. Twenty-three thumbs were considered suitable for replantation. A staged approach, consisting of primary replantation and secondary nerve grafting and tendon reconstruction, was used because of concern that survival rates would be low. Survival was achieved in nineteen of twenty-three replantations. At mean follow-up of 20.5 months grip strength was 94.6% of the unaffected side and key pinch was 77.1%. Five patients achieved a two-point discrimination less than five millimeters. Success was better anticipated and now a full reconstruction is carried out in a single-stage procedure.

Computed tomography of wrist trauma.

We devised a rapid and sensitive computed tomography (CT) method to assess the acutely injured wrist, healing carpal fractures and post-traumatic osteonecrosis, when the plain films offer insufficient information. The wrist is positioned in a simple reverse-L-shaped Perspex immobilizer. With the scaphoid as the center of the arc and the long axis of the distal radius as the reference 0 degrees line, sequential coronal scans of the wrist were done in 10 degrees increments in an arc of 40 degrees to give 0 degrees, 10 degrees, 20 degrees, 30 degrees and 40 degrees scans. The 0 degrees and 10 degrees arc scans were best for evaluating the distal radius and ulna and soft tissues, the 10 degrees and 20 degrees scans for the carpal bones other than the scaphoid, and their relation to each other, the 30 degrees and 40 degrees scans, parallel to the long axis of the scaphoid, for fractures of the scaphoid and the hook of the hamate. In addition the 40 degrees scan offered an excellent carpal tunnel view. In 22 patients examined for wrist trauma CT was found to be more accurate than plain films and plain-film tomography in determining the presence of a fracture (4 scaphoid and 1 distal radius), in assessing the degree of osseous union (12) and in evaluating intercarpal fusion (2). In addition CT detected avascular necrosis of the lunate in two patients and erosions of the scaphoid and distal radius attributed to rheumatoid arthritis in one.

Forty degree angled coronal CT scanning of scaphoid fractures through plaster and fiberglass casts.

A method for obtaining coronal CT scans angled 40 degrees to the longitudinal axis of the wrist, parallel to the long axis of the scaphoid, is described. Its potential for evaluating scaphoid fractures is assessed in 10 patients with healing or clinically suspected fractures. Overlapping 3 mm thick angled coronal CT scans were obtained for each patient both in and out of cast. The CT images were compared to plain films and tomography. Comparisons were also made of CT images obtained through fiberglass and plaster casts. All fractures apparent by plain films and tomography were apparent by CT; one case suspected of fracture on initial plain films showed no evidence of fracture on CT and subsequent clinical course and plain films. Osseous union of healing fractures was more reliably assessed on CT than on plain films and plain film tomography. There was no degradation of CT images by either fiberglass or plaster casts; fiberglass casts allowed easy planning of tomographic slices from scout films. We conclude that direct 40 degree angled coronal CT examination of the scaphoid is a quick reliable method to detect scaphoid fractures and to assess their healing without the need of cast removal.

Attritional flexor tendon ruptures by an old lunate dislocation.

A 76-year-old man sustained attritional disruption of the extrinsic flexor tendons to the ulnar two fingers over 40 years after an untreated palmar lunate dislocation. Spontaneous flexor tendon rupture is rare without wrist joint pathology, even in the absence of chronic pain or median nerve compression.

Transfer of free vascular cutaneous flaps by microvascular anastomosis. Results in six dogs.

Skin defects on the distal extremities of six dogs were reconstructed with free vascular cutaneous transfers by microvascular anastomosis. The donor flaps were based on the superficial cervical artery and vein. In five of the dogs, bone was exposed and skin was lost from half of the circumference of the limb. Two had infected fractures with sequestra and three had acute shearing injuries. The sixth dog had sensory denervation of the left antebrachium and a carpal acral lick granuloma. Before surgery, the patency of potential recipient vessels was confirmed with arteriography in five dogs and an ultrasonic doppler in one dog. Microvascular technique was used to reestablish circulation to the flaps after they were transferred to the recipient site. Total ischemic time of the flaps averaged 100 minutes. All flaps survived. Successful reconstruction of the cutaneous defects was achieved in these six cases.

Excision of pisiform in pisotriquetral arthritis.

Eight patients (nine cases) with pisotriquetral arthritis were treated by pisiform excision after they had failed to respond to splints, antiinflammatory agents, and local steroid injection. Associated with pisotriquetral arthritis were cases of ulnar neuritis, rheumatoid arthritis, pisotriquetral joint loose bodies, and an anomalous muscle. In seven of eight patients, pisiform excision with release of Guyon's canal afforded prompt relief of pain. A palmar approach was necessary for simultaneous ulnar tunnel release and pisiform excisions. One patient with rheumatoid arthritis required a further operative procedure (Darrach) before pain was eliminated. Pisotriquetral arthritis, diagnosed by clinical and radiographic criteria, may be associated with other disorders, in particular ulnar neuritis. Immobilization, antiinflammatories, and local steroid injections may be of temporary assistance. Pisiform excision produces satisfactory relief of pain.

A complication of posterior glenoid osteotomy for recurrent posterior shoulder instability.

Posterior glenoid osteotomy (posterior glenoplasty) is a standard surgical reconstructive operation for recurrent posterior instability of the shoulder. A 34-year-old man was treated by glenoid osteotomy and subsequently developed significant glenohumeral arthritis. Following several surgical procedures, only total shoulder arthroplasty gave substantial pain relief and restored stability. Inadvertent penetration of the glenohumeral joint at the time of osteotomy may have predisposed the patient to glenohumeral arthritis. Extreme care should be exercised not to damage the shoulder joint during this procedure.

Report on use of XAD resins in racing chemistry.

This report comprises a summary of the work done with XAD resin extraction by racing chemists and reported in the Association of Official Racing Chemists publications. It is apparent that the use of XAD resins is becoming more popular in racing laboratories as a technique for routine screening and also for the extraction of certain conjugated drugs. Most laboratories employ variations on the original Brinkmann Drug-Skreen Technique. Comparisons of the efficiency of extraction of drugs from horse urine by XAD-2 resin and by chloroform column extraction indicate that some drugs can be extracted with equal or greater efficiency by the resin technique.