[Clinical-imaging-arthroscopic correlation in the diagnosis of meniscal lesions]. / Correlación clínica - imagenológica - artroscópica en el diagnóstico de las lesiones meniscales.

OBJECTIVE: To assess the relation between location and intensity of pain in the articular interline as reported by the patient and proven objectively with the physical exam, and the type and location of the meniscal lesion found in the knee imaging study and arthroscopy. METHOD: Prospective, observational, longitudinal study including 34 consecutive patients with a clinical and arthroscopic diagnosis of symptomatic meniscal tears. Pain location was reported, an MRI was taken and finally all patients were assessed with knee arthroscopy. RESULTS: We found an excellent correlation between the clinical manifestation of pain and the arthroscopic findings (p < 0.001), as well as between the clinical findings and the MRI (p < 0.001). CONCLUSION: Correlating the clinical expression of meniscal pathology with the anatomical lesion could be useful at the time of deciding to perform surgery, as the clinical identification of certain types of meniscal tears could potentially determine what the best time to perform surgery is. Our study shows that there is no significant relation neither between the magnitude of pain and the laterality of the lesion, nor between the magnitude of pain and the type of lesion diagnosed arthroscopically. This shows that patients cannot be selected considering the anatomy of the lesion based only on the physical exam.

Conformational preferences in a benzodiazepine series of potent nonpeptide fibrinogen receptor antagonists.

Previously, we reported the direct design of highly potent nonpeptide 3-oxo-1,4-benzodiazepine fibrinogen receptor antagonists from a constrained, RGD-containing cyclic semipeptide. The critical features incorporated into the design of these nonpeptides were the exocyclic amide at the 8-position which overlaid the Arg carbonyl, the phenyl ring which maintained an extended Gly conformation, and the diazepine ring which mimicked the gamma-turn at Asp. In this paper, we investigate conformational preferences of the 8-substituted benzodiazepine analogues by examining structural modifications to both the exocyclic amide and the seven-membered diazepine ring and by studying the conformation of the benzodiazepine ring using molecular modeling, X-ray crystallography, and NMR. We found that the directionality of the amide at the 8-position had little effect on activity and the (E)-olefin analogue retained significant potency, indicating that the trans orientation of the amide, and not the carbonyl or NH groups, made the largest contribution to the observed activity. For the diazepine ring, with the exception of the closely analogous 3-oxo-2-benzazepine ring system described previously, all of the modifications led to a significant reduction in activity compared to the potent 3-oxo-1, 4-benzodiazepine parent ring system, implicating this particular type of ring system as a desirable structural feature for high potency. Energy minimizations of a number of the modified analogues revealed that none could adopt the same low-energy conformation as the one shared by the active (S)-isomer of the 3-oxo-1, 4-benzodiazepines and 3-oxo-2-benzazepines. The overall data suggest that the features contributing to the observed high potency in this series are the orientation of the 3-4 amide and the conformational constraint imposed by the seven-membered ring, both of which position the key acidic and basic groups in the proper spatial relationship.

Benzimidazole derivatives as arginine mimetics in 1,4-benzodiazepine nonpeptide vitronectin receptor (alpha v beta 3) antagonists.

In a 3-oxo-1,4-benzodiazepine-2-acetic acid series of vitronectin receptor (alpha v beta 3) antagonists containing a benzimidazole as a novel arginine mimetic, we examined the effects of benzimidazole modifications and amide substitutions on both activity and pharmacokinetics.

Conformationally constrained peptides and semipeptides derived from RGD as potent inhibitors of the platelet fibrinogen receptor and platelet aggregation.

Structure-activity studies have been pursued on cyclo-S,S-[Ac-Cys-(N alpha-Me)Arg-Gly-Asp-Pen]-NH2, 2 (SK&F 106760), a potent inhibitor of platelet aggregation, in an effort to improve potency and affinity for the GPIIb/IIIa receptor. Modifications on the N- and C-termini of 2 produced a series of peptides which indicate that the C-terminal carboxylate group may be a secondary receptor-binding element. Further modification by replacing the disulfide tether N alpha-acetylcysteine/penicillamineamide with the novel, inexpensive, achiral, constrained, and more lipophilic tether 2-mercaptobenzoyl/2-mercaptoaniline (Mba/Man) afforded the semipeptide cyclo-S,S-[Mba-(N alpha-Me)Arg-Gly-Asp-Man], 18 (SK&F 107260), which exhibited significant enhancement in both affinity and potency. To further investigate the effect of the phenyl ring at the C-terminus, peptides bearing the novel (2R,3S)- and (2R,3R)-beta-phenylcysteines were synthesized, which culminated in the cyclo-S,S-[Ac-Cys-(N alpha-Me)Arg-Gly-Asp-(2R,3S)-beta-phenylCys]-OH peptide, 22, which displayed substantial affinity and potency. We describe, herein, the development of both 18 and 22 and the additional structural modifications within the constrained cyclic disulfide ring to probe the stereochemical and steric requirements for receptor interaction.

Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives.

Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.