The need for new antimicrobial agents is greater than ever because of the emergence of multidrug resistance in common pathogens, the rapid emergence of new infections, and the potential for use of multidrug-resistant agents in bioweapons. Paradoxically, some pharmaceutical companies have indicated that they are curtailing anti-infective research programs. We evaluated the United States Food and Drug Administration (FDA) databases of approved drugs and the research and development programs of the world's largest pharmaceutical and biotechnology companies to document trends in the development of new antimicrobial agents. FDA approval of new antibacterial agents decreased by 56% over the past 20 years (1998-2002 vs. 1983-1987). Projecting future development, new antibacterial agents constitute 6 of 506 drugs disclosed in the developmental programs of the largest pharmaceutical and biotechnology companies. Despite the critical need for new antimicrobial agents, the development of these agents is declining. Solutions encouraging and facilitating the development of new antimicrobial agents are needed.

Patients with atherosclerotic peripheral arterial disease (PAD) of the lower extremities have impaired walking ability due to exercise-induced muscle ischemia and the resultant pain of intermittent claudication. To evaluate the benefit of exercise training as a treatment for patients with PAD, as well as possible mechanisms associated with improvement, we randomly assigned 19 men with disabling claudication to treated and control groups. Treatment consisted of supervised treadmill walking (1 hr/day, 3 days/wk, for 12 weeks) with progressive increases in speed and grade as tolerated. Graded treadmill testing was performed to maximal toleration of claudication pain on entry and after 12 weeks of training to define changes in peak exercise performance. After 12 weeks, treated subjects had increased their peak walking time 123%, peak oxygen consumption 30%, and pain-free walking time 165% (all p<0.05). Control subjects had no change in peak oxygen consumption, but after 12 weeks, peak walking time increased 20% (p<0.05). In treated subjects, maximal calf blood flow (measured by a plethysmograph) increased 38+45% (p<0.05), but the change in flow was not correlated to the increase in peak walking time. Elevated plasma concentrations of acylcarnitines have been associated with the functional impairment of PAD and may reflect the metabolic state of ischemic skeletal muscle. In treated subjects, a 26% decrease in resting plasma short-chain acylcarnitine concentration was correlated with improvement in peak walking time (r= -0.78, p <0.05). Thus, 12 weeks of exercise training for patients with PAD improved peak exercise performance and claudication pain severity, which in part may be due to an improvement in skeletal muscle oxidative metabolism. (Circulation 1990;81:602-609) A therosclerotic peripheral arterial disease (PAD) of the lower extremities, when associated with intermittent claudication, results in a moderate-to-severe impairment in walking ability. Patients with PAD are unable to walk more than a short distance on level ground and have a severely limited peak exercise capacity during graded treadmill exercisel-4 in a range that allows for only very light to light activities.5 As a result, the energy requirements of many leisure-and work-related tasks exceed the peak exercise capacity of these patients.Exercise training has been shown to improve walking ability on level ground6-8 and during constant-

BACKGROUND Peripheral arterial disease (PAD) is associated with an impairment in exercise performance and muscle function that is not fully explained by the reduced leg blood flow during exercise. This study characterized the effects of PAD on muscle function, histology, and metabolism. METHODS AND RESULTS Twenty-six patients with PAD and six age-matched control subjects were studied. Ten of the PAD patients had unilateral disease, which permitted paired comparisons between their diseased and nonsymptomatic legs. All PAD patients had a lower peak treadmill walking time and peak oxygen consumption than controls. Vascular disease (diseased leg in unilateral patients and the most severely diseased leg in bilateral patients) was associated with decreased calf muscle strength compared with control values. In patients with unilateral disease, the diseased legs had a greater percentage of angular fibers (indicating chronic denervation) and a decreased type II fiber cross-sectional area (expressed as percent of total fiber area) compared with the nonsymptomatic, or control, legs. In diseased legs, gastrocnemius muscle strength was correlated with the total calf cross-sectional area (r = 0.78, p < 0.05) and type II fiber cross-sectional area (r = 0.63, p < 0.05). Activities of citrate synthase, phosphofructokinase, and lactate dehydrogenase in all 26 PAD patients (most diseased leg) did not differ from control values. Despite a wide range in citrate synthase activity in PAD patients, activity of this enzyme was not correlated with muscle strength or treadmill exercise performance. CONCLUSIONS In patients with PAD, gastrocnemius muscle weakness is associated with muscle fiber denervation and a decreased type II fiber cross-sectional area. In contrast, the PAD patients displayed substantial heterogeneity in muscle enzyme activities that was not associated with exercise performance. Denervation and type II fiber atrophy may contribute to the muscle dysfunction in patients with PAD and further confirm that the pathophysiology of chronic PAD extends beyond arterial obstruction.

Among these ambulatory ESRD patients, peak VO2 was a stronger predictor of survival than many traditional prognostic variables, some of which are subject to ceiling effects. Exercise capacity may thus provide incremental prognostic information concerning healthier ESRD patients. Because peak VO2 may be modified by exercise training, the potential of exercise as an intervention to improve survival is suggested.