Beach chair position with instrumental distraction for arthroscopic and open shoulder surgeries.

Arthroscopy is widely used in the diagnosis and treatment of shoulder disorders. It can be performed in the lateral or sitting position (beach chair). Both have advantages and disadvantages. We present a simple, inexpensive, versatile, portable, continuous distraction device for arthroscopic, combined, and open shoulder surgeries in the sitting position that offers the advantages of the 2 classic positions without their disadvantages. The device was used in 101 consecutive procedures: 61 rotator cuff repairs (29 arthroscopic, 18 mini-open, 14 open), 4 two-part humeral fractures, 1 septic arthritis, 3 calcifying tendinitis, 9 capsular releases, 8 Bankart repairs (6 arthroscopic, 2 open), 13 acromioplasty and biceps tenotomy, and 2 superior labrum anteroposterior repairs. Our experience with this device is extremely positive. We have had no complications and have used it for shoulder arthroscopy, open, and combined surgeries. We have also not had difficulty visualizing or approaching the glenohumeral and subacromial spaces in the treatment of shoulder disorders. It is a safe, practical, easy, and fast set up. Its versatility makes it particularly helpful for the less experienced arthroscopic surgeon.

Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: rapid structure-activity studies by solid-phase synthesis.

Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.

Potent noncovalent thrombin inhibitors that utilize the unique amino acid D-dicyclohexylalanine in the P3 position. Implications on oral bioavailability and antithrombotic efficacy.

In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.

Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position.

As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460): coapplication of structure-based design and rapid multiple analogue synthesis on solid support.

Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties via a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P2-P1 template 7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)-prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, Ki = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 micrograms/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to further evaluation as a possible treatment for thrombogenic disorders.

Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position.

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.

Efficacious, orally bioavailable thrombin inhibitors based on 3-aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates.

We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.

The hook test for distal biceps tendon avulsion.

BACKGROUND: Complete biceps tendon avulsions are frequently missed on clinical examination, suggesting the need for a reliable diagnostic test. HYPOTHESIS: Complete distal biceps avulsions can be reliably detected with the Hook test. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: The hook test was performed by a single surgeon in a cohort of 45 patients undergoing surgical exploration of the distal biceps tendon. While the patient actively supinates with the elbow flexed 90 degrees , an intact hook test permits the examiner to hook his or her index finger under the intact biceps tendon from the lateral side. With an abnormal hook test, indicating distal avulsion, there is no cord-like structure under which the examiner may hook a finger. RESULTS: Thirty-three patients had an avulsion and 12 had a partial tear. The hook test was abnormal in 33 of 33 (100%) patients with complete biceps avulsions, and intact in 12 of 12 with partial detachments. However, it was painful in 9 of those 12. In the noninjured contralateral arms, which served as the normal control group, 45 of 45 (100%) had a normal hook test. Magnetic resonance imaging (MRI) diagnosed a complete tear in 11 of 12 patients with partial tears and in 11 of 13 with complete lesions. The sensitivity and specificity were both higher with the hook test (both 100%) than with MRI (92% and 85%, respectively). CONCLUSIONS: The hook test is a highly sensitive and specific test for assessment of distal biceps tendon avulsions.

Acute lung injury induced by Pseudomonas aeruginosa elastase in hamsters.

Human neutrophil elastase (HNE) is the predominant elastolytic enzyme in the sputum of cystic fibrosis (CF) patients. However, a variably small portion of the activity can be ascribed to Pseudomonas aeruginosa elastase (PaE). The purpose of these studies was to evaluate the activities of the two elastases in an in vivo model of acute lung injury (ALI). The elastolytic activity of Pseudomonas aeruginosa elastase (MW = 39K) and human neutrophil elastase (MW = 33K) were also examined using insoluble bovine neck and lung elastin. The ability of hamster serum to inhibit elastinolysis by the two elastases was also examined. On a per milligram protein basis, PaE was the more potent elastase, regardless of substrate, and it preferentially hydrolyzed lung relative to neck elastin. PaE is poorly inhibited by hamster serum compared to HNE. In vivo, PaE is much more efficient than HNE in inducing an acute lung injury in hamsters. The duration of effects induced by doses of the two proteases that produce similar acute biological effects are essentially identical. The increases of lung weight and total lavagable WBCs persist for at least 7 days. All other parameters return to baseline between 3 and 5 days. The predominant cells in the lavage 1 and 2 days post insult are PMNs. By day 7, the predominant cell is the macrophage. These data suggest that even though PaE is a minor component of the elastolytic activity in CF patients, it may still contribute significantly to the pathology of the disease.

Characterization of the two-step pathway for inhibition of thrombin by alpha-ketoamide transition state analogs.

The interaction of thrombin with several potent and selective alpha-ketoamide transition state analogs was characterized. L-370, 518 (H-N-Me-D-Phe-Pro-t-4-aminocyclohexylglycyl N-methylcarboxamide) a potent (Ki = 90 pM) and selective (>10(4)-fold versus trypsin) ketoamide thrombin inhibitor was shown to bind thrombin via a two-step reaction wherein the initially formed thrombin-inhibitor complex (EI1) rearranges to a more stable, final complex (EI2). A novel sequential stopped-flow analysis showed that k-1, the rate constant for dissociation of EI1, was comparable to k2, the rate constant for conversion of EI1 to EI2 (0.049 and 0.035 s-1, respectively) indicating that formation of the initial complex EI1 is partially rate controlling. Replacement of the N-terminal methylamino group in L-370,518 with a hydrogen (L-372,051) resulted in a 44-fold loss in potency (Ki = 4 nM) largely due to an increase in k-1. Consequently in the reaction of L-372,051 with thrombin formation of EI1 was not rate controlling. Replacement of the P1' N-methylcarboxamide group of L-370,518 with an azetidylcarboxamido (L-372,228) produced a 58-fold increase in the value of the equilibrium constant (K-1) for dissociation of EI1. Nevertheless, L-372,228 was a 2-fold more potent thrombin inhibitor (Ki = 40 pM) than L-370,518 due to its 16-fold higher k2 and 10-fold lower k-2 values. The desketoamide analogs of L-370,518 and L-372,051, namely L-371,912 and L-372,011, inhibited thrombin via a one-step process. The Ki value for L-371,912 and the K-1 value for its alpha-ketoamide analog, L-370,518, were similar (5 and 14 nM, respectively). Likewise, the Ki value for L-372,011 and the K-1 value for its alpha-ketoamide analog, L-372,051, were similar (330 and 285 nM, respectively). These observations are consistent with the view that the alpha-ketoamides L-370,518 and L-372,051 form initial complexes with thrombin that are similar to the complexes formed by their desketoamide analogs, and in a second step the alpha-ketoamides react with the active site serine residue of thrombin to form a more stable hemiketal adduct.

Bicyclic pyridones as potent, efficacious and orally bioavailable thrombin inhibitors.

A new class of conformationally constrained thrombin inhibitors is described. These compounds contain a unique bicyclic pyridone scaffold which serves as a P3P2 dipeptide surrogate. The synthesis and antithrombotic activity of these inhibitors is reported.

L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor.

Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, Ki = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography.