Effect of heel lifts on plantarflexor and dorsiflexor activity during gait.

BACKGROUND: Previous investigators have shown that high heels decrease the muscle activity of the gastrocnemius muscle during gait. However, it is not known whether commonly used in-shoe heel lifts of lower heights will demonstrate similar effects on muscle activity. The aim of this study was to determine whether heel lifts alter the muscle activity of the ankle plantarflexors and dorsiflexors during the stance phase of gait among individuals with limited gastrocnemius extensibility. MATERIALS AND METHODS: This study used a repeated measures design. Twenty-four healthy volunteers (12 males and 12 females) with less than 5 degrees of passive ankle dorsiflexion with the knee extended participated in the study. Electromyography (EMG), computerized motion analysis, and a force plate were used to measure mean muscle activity of the lateral gastrocnemius, medial gastrocnemius, soleus and tibialis anterior muscles during the stance phase of gait across three walking conditions. Muscle activity was measured as participants ambulated at a self-selected speed in athletic shoes alone and with heel lifts of 6 mm and 9 mm inserted in athletic shoes. RESULTS: Between heel-strike and heel-off, the mean EMG amplitude of the medial gastrocnemius increased with both 6 and 9 mm heel lifts and the amplitude of the tibialis anterior increased with 9 mm heel lifts compared to shoes alone. Between heel-strike and heel-off, there were no significant differences in mean EMG amplitude of the lateral gastrocnemius or soleus muscles walking in heel lifts compared to shoes alone. Between heel-off and toe-off, there were no significant differences in mean EMG amplitude of the lateral gastrocnemius, medial gastrocnemius, soleus, or tibialis anterior muscles when walking in heel lifts compared to shoes alone. CONCLUSION: Heel lifts increase muscle activity of the medial gastrocnemius and tibialis anterior muscles between heel-strike and heel-off among individuals with limited gastrocnemius extensibility. CLINICAL RELEVANCE: We were unable to confirm a decrease in muscle activity when using heel lifts.

Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice.

Accumulating evidence demonstrates that dietary intake of n-3 polyunsaturated fatty acids (PUFAs) is associated with reduced incidence of cardiovascular events. However, the molecular mechanisms by which n-3 PUFAs prevent atherosclerosis are not fully understood. Here, we examined the effect of eicosapentaenoic acid (EPA), a major n-3 PUFA, on the pathogenesis of atherosclerosis in ApoE-deficient mice. Five-week-old ApoE-deficient male mice were fed on western-type diet supplemented with 5% (w/w) EPA (EPA group, n=7) or not (control group, n=5) for 13 weeks. An analysis of the fatty acid composition of liver homogenates revealed a marked increase of the n-3 PUFA content in the EPA group (n-3/n-6 ratio: 0.20+/-0.01 vs. 2.5+/-0.2, p<0.01). En face Sudan IV staining of the aorta and oil red O-staining of the aortic sinus revealed that EPA significantly suppressed the development of atherosclerotic lesions. We also observed anti-atherosclerotic effects of EPA in LDL-receptor-deficient mice. The lesions of the EPA group contained more collagen (19.6+/-2.4% vs. 32.9+/-3.9%, p<0.05) and smooth muscle cells (1.3+/-0.2% vs. 3.6+/-0.8%, p<0.05) and less macrophages (32.7+/-4.1% vs. 14.7+/-2.0%, p<0.05). Pretreatment with EPA attenuated the up-regulation of VCAM-1, ICAM-1 and MCP-1 in HUVECs as well as the expression of MMP-2 and MMP-9 in macrophage-like cells induced by TNF-alpha. The anti-inflammatory effects of EPA were abrogated when the expression of peroxisome proliferator-activated receptor alpha (PPARalpha) was suppressed. EPA may potentially reduce and stabilize atherosclerotic lesions through its anti-inflammatory effects.

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors(1-6) VI. A series of new derivatives containing N,S- and N,SO2-spiro acetal scaffolds.

In the course of development of factor Xa (FXa) inhibitors, we have found unique compounds containing an N,O- and an N,N-spiro acetal structure. It appeared that the difference in overall conformation due to the N,X-spiro acetal structure might be important for FXa inhibitory activity. Therefore, other N,X-spiro acetal structures, an N,S- and an N,SO2-spiro acetal, were developed as analogues of the N,X-spiro acetal structure. Compound 7b (N,S-spiro acetal structure) was found to have the strongest activity in these series of N,X-spiro acetal compounds, which had ever been synthesized.(4,5)).

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors V. A series of new derivatives containing a spiro[imidazo[1,2-a]pyrazine-2(3H),4'-piperidin]-5(1H)-one scaffold.

We have already reported unique compounds containing a N,O-spiro acetal structure as an orally active factor Xa (FXa) inhibitor. This time, we described a N,N-spiro acetal structure as an analogue of the N,O-spiro acetal structure for an orally active FXa inhibitor. The synthesis of these analogues could be achieved in a similar fashion to the N,O-spiro acetal synthesis. Consequently, FXa inhibitory activity was increased and more active compounds could be found (M58163: IC50 = 0.61 nM, M58169: IC50 = 0.58 nM). Additionally, the absolute configuration could be determined by X-ray crystallography analysis (M58169: (R)-config.).

Pharmacological characterization of the active synthetic factor Xa inhibitors M55551 and M55165.

Factor Xa plays an important role in blood coagulation and is widely regarded as an attractive target for antithrombotic drug development. M55551 and M55165 (1-arylsulfonyl-3-piperazinone derivatives) are novel synthetic factor Xa inhibitors. In vitro, M55551 and M55165 competitively inhibited factor Xa with K(i) values of 3.2 nM and 2.3 nM, respectively, and prolonged clotting time in human and rat plasma. Pharmacokinetic analysis of these compounds revealed that M55551 was intravenously active with a short half-life (0.2 h) and that M55165 exhibited good bioavailability (31%) with a long half-life (3.9 h). Therefore, the antithrombotic effects of M55551 and M55165 were compared with those of the intravenous anticoagulant argatroban and the oral anticoagulant warfarin. Intravenous administration of M55551 and oral administration of M55165 inhibited thrombus formation at 0.3 mg/kg and 10 mg/kg, respectively, without significant prolongation of bleeding time. In contrast, although argatroban (0.3 mg/kg) and warfarin (1 mg/kg) also inhibited thrombus formation, significant prolongation of bleeding time was observed at dosages of 3 mg/kg and 1 mg/kg, respectively. These results suggest that M55551 and M55165 are potent factor Xa inhibitors that are active upon intravenous and oral administration, respectively, and that may prove clinically useful for the treatment of thrombosis while minimizing bleeding risks.

Relation between variability of ventricular response intervals and exercise capacity in patients with non-valvular atrial fibrillation.

BACKGROUND: Reduced variability of the ventricular response interval (VRI) has been reported to predict adverse prognosis in patients with atrial fibrillation (AF). To examine whether it could be related also to the quality of the daily life of patients with AF, the relationships between VRI variability and exercise tolerance, one of the markers for quality of life, were determined in patients with persistent AF. METHODS AND RESULTS: Thirty-one patients with idiopathic AF were included in the present study. Holter monitoring results and symptom-limited treadmill exercise testing were correlated in these patients without medications for the rate control of AF. The VRI variability, both the SD of the mean R-R interval (SDNN) and the SD of the 5-min mean R-R interval (SDANN), showed significant positive correlation with the exercise capacity (r=0.583, p=0.0004, and r=0.543, p=0.0013, respectively), whereas age, left ventricular ejection fraction and body mass index did not have any significant relationships. Multiple regression analysis revealed that increased SDNN was the only independent predictor of good exercise capacity during the treadmill exercise testing. CONCLUSIONS: Increased VRI variability, independently of other clinical variables, can predict good exercise capacity in patients with idiopathic AF, thus being a new sensitive maker for quality of life in AF.

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors IV. A series of new derivatives containing a spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one skeleton.

In the course of development of factor Xa (FXa) inhibitor in an investigation involving the synthesis of 1-arylsulfonyl-3-piperazinone derivatives, we found new compounds containing a unique spiro skeleton. Among such compounds, (-)-7-[(6-chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-1'-(4-pyridinyl)-spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one (28, M55529) had activity more favorable than those of previously reported compounds. The inhibitory activity of M55529 for FXa is IC(50)=2 nM, with high selectivity for FXa over thrombin and trypsin.

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors III. Effect of ring opening of piperazinone moiety on inhibition.

Compounds containing an ethylenediamine structure in place of the piperazine ring of M55113 (1) and M55551 (2) were synthesized to investigate the effects of a piperazine moiety and evaluated for activity as factor Xa (FXa) inhibitors. Most such compounds, however, exhibited lower activity (1/10-1/100) than that of M55113 and M55551 as FXa inhibitors.

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities.

Intravascular clot formation is an important event in a number of cardiovascular diseases. The prevention of blood coagulation has become a major target for new therapeutic agents. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. We have investigated substituents in the central part of a lead compound (3: M55113), and discovered that compound M55551 (34: (R)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylic acid) is a potent inhibitor of FXa (IC(50)=0.006 microM), with high selectivity for FXa over trypsin and thrombin. The activity of this compound is ten times more powerful than the lead compound.