Antiinflammatory and analgesic activity of an inhibitor of neuropeptide amidation.

4-Phenyl-3-butenoic acid (PBA) has been shown in vitro to be a turnover-dependent inactivator of peptidylglycine alpha-monooxygenase (PAM), the rate-limiting enzyme involved in the formation of amidated neuropeptides from their glycine-extended precursors. In the studies reported herein, we have shown that PBA produces a dose-dependent (50-500 mg/kg s.c.) inhibition of serum PAM activity in normal rats without affecting peptidylamidoglycolate lyase activity. Because amidated neuropeptides such as substance P and calcitonin gene-related peptide are involved in acute inflammation, we evaluated the effects of PBA on carrageenan-induced inflammation in rats. The acute administration of PBA (s.c. or i.p.) produced a dose-related inhibition of edema with maximum inhibition (67%) observed at 2 hr postphlogistic agent. In addition, the continuous administration of PBA to animals over a 7-day period using osmotic pumps not only inhibited hind paw swelling induced by carrageenan but also inhibited serum PAM activity and reduced tissue levels of substance P in hind paws. These results demonstrate for the first time a correlation between the antiinflammatory activity produced by an inhibitor of peptide amidation with its ability to inhibit serum PAM activity and lower endogenous tissue levels of substance P. Moreover, these results confirm our contention that PAM is an excellent pharmacological target for controlling the acute inflammatory response. We also demonstrate the ability of PBA to inhibit phenyl-p-quinone and acetylcholine-induced writhing in mice without affecting the spinally mediated tail immersion assay in rats. Because this analgesic effect was extremely rapid (within 15 min), PBA may be producing this effect by a mechanism other than peptide amidation.

Coronary heart disease prevention in childhood: one-year results of a randomized intervention study.

A six-year intervention study of the feasibility and effectiveness of a program aimed at the primary prevention of coronary heart disease (CHD) has been initiated among children in six school districts in Westchester County, New York. Schools randomly were assigned either to the intervention program or to a control group. The intervention program consists of a curriculum focusing on nutrition, physical fitness, and cigarette smoking prevention. The study population at baseline comprised 1,822 fourth-graders. This paper presents the findings at baseline and at one-year follow-up for the following target risk factors: systolic and diastolic blood pressure, plasma total and high-density lipoprotein (HDL) cholesterol, serum thiocyanate, ponderosity index, triceps skinfold thickness, and postexercise pulse recovery rate. After one year of intervention, the program was found to be acceptable to school administrators, teachers, parents, and children. Small net changes in the favorable direction were observed for diastolic blood pressure and thiocyanate. Intervention programs in schools may, after sufficient duration, prove to be effective in lowering CHD risk.

Primary prevention of chronic disease in childhood: changes in risk factors after one year of intervention.

A five-year intervention study of the feasibility and effectiveness of a program aimed at the primary prevention of chronic disease was initiated in 1980 among children in 22 elementary schools in the Bronx, New York. Schools randomly were assigned either to the intervention program or to a control group. The intervention program consists of a curriculum focusing on nutrition, physical fitness, and cigarette smoking prevention. The study population at baseline comprised 2,283 fourth-graders. Subjects were eligible at baseline and at one-year follow-up for participation in a medical examination in which the following target risk factors were measured: systolic and diastolic blood pressures, plasma total and high-density lipoprotein (HDL) cholesterol, serum thiocyanate, ponderosity index, triceps skinfold thickness, and postexercise pulse recovery rate. After one year of intervention, systolic pressure increased less in the intervention group than among controls. Diastolic pressure decreased in both groups, but more in the intervention subjects than in controls. Total cholesterol decreased in the intervention group while increasing among controls. Significant net changes in the favorable direction also were observed for total cholesterol/HDL cholesterol ratio and for thiocyanate. These observations indicate that it is feasible to implement a school-based program aimed at the primary prevention of chronic disease. The intervention program appears to have had a favorable effect on several target risk factors. Although the effects were relatively small, intervention programs in schools may prove to be effective in lowering chronic disease risk.