Acylguanidines as bioisosteres of guanidines: NG-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists.

N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.

Moving objects in a rotating environment: rapid prediction of Coriolis and centrifugal force perturbations.

Grip force adaptation to Coriolis and centrifugal force perturbations was tested in healthy subjects. Eight subjects were seated in a rotating chamber in a rotating axis position. They each grasped an instrumented object resting on the thumb, which was stabilized by the other fingers from above. Subjects performed horizontal point-to-point movements with the grasped object away and towards the trunk. These movements were directed in a nonparallel fashion towards the axis of rotation prior (40 pre-rotational movements), during (80 per-rotational movements) and following (40 post-rotational movements) clockwise body rotation. During pre- and post-rotational movements two load force peaks of similar magnitude occurred during the acceleratory and deceleratory phases of the movements. Accordingly, a Coriolis force, which was orthogonal and proportional to the linear velocity of the moving arm, as well as a centrifugal force proportional to the system's squared angular velocity and movement amplitude developed during per-rotational movements. The load perturbations altered the load force profile in a characteristic way. The first 10 per-rotational movement sequence revealed that there was a less precise coupling between grip and load force magnitudes and a reduced temporo-spatial co-ordination between grip and load force profiles. With increasing number of per-rotational movements, there was significant improvement in the temporo-spatial co-ordination and in the coupling in force magnitude between grip and load force profiles, indicating an ongoing adaptation process. The coupling between grip and load forces proved to be similarly precise for the last 10 per-rotational movements and for pre-rotational movements, suggesting complete adaptation. Significant effects were observed for the first post rotational movements following adaptation to the per-rotational load characteristics both for the temporal co-ordination between grip and load forces and for the coupling in force magnitudes. However, the last 10 post-rotational movements proved to be similarly precise with comparison to pre-rotational performance in terms of grip force regulation with movement-induced loads. The results are discussed within the context of the CNS ability to use internal models when planning and processing anticipatory grip force adjustments during manipulative tasks.

A biomechanical evaluation of methods of distal humerus fracture fixation using locking compression plates versus conventional reconstruction plates.

OBJECTIVES: To examine the biomechanical behavior of 2 techniques of double-plate osteosynthesis for fractures of the adult distal humerus using conventional reconstruction plates and locking compression plates. DESIGN: Basic science study. SETTING: Experimental in vitro study. PATIENTS/PARTICIPANTS: Forty fresh-frozen human distal humeri specimens. INTERVENTION: Four matched groups with 10 humeri each, median age 74 years (46-95), were created using similar bone mineral density values. Two standard configurations of double-plate osteosynthesis (dorsal or 90 degrees configuration) with either conventional reconstruction plates or locking compression plates were studied for biomechanical properties of the constructs. A fracture model with a 5-mm supracondylar osteotomy gap simulating metaphyseal comminution (AO type 13-A3.3) was used. MAIN OUTCOME MEASUREMENT: Stiffness testing of the constructs in anterior/posterior bending, torsion, and axial compression loading. Evaluation of alterations of the bone-implant interface and failure patterns under cyclic loading and strength testing. RESULTS: The study demonstrates that primary stiffness in anterior/posterior bending and torsional loading is significantly increased by using locking compression plates in a 90 degrees configuration (P < 0.05) as compared with dorsally applied plates. The differences between the different plate types are insignificant if applied in the same configuration. It is demonstrated that none of the tested implants failed under cyclic loading within the number of cycles expected for 3 months of use. The bone-implant interface is less likely to fail during strength testing with locking compression plates. CONCLUSION: The biomechanical behavior of the osteosynthesis depends more on plate configuration than plate type. Advantages of locking compression plates are only significant if compared with dorsal plate application techniques. Nevertheless, locking compression plates are helpful supplementary tools for achieving primary stable fracture fixation. This might be of considerable clinical relevance in patients with diminished bone mineral quality or in the presence of metaphyseal comminution.