valyl-prolyl-proline and Body-Weight

A double-blind, placebo-controlled, randomized clinical trial was conducted to evaluate the effects of ingesting an excess of tablets containing casein hydrolysate, incorporating angiotensin I-converting enzyme (ACE) inhibitory peptides such as Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), in subjects with blood pressure ranging from normal to mild hypertension. A total of 48 subjects were given either 5 times more than the effective amount of casein hydrolysate or a placebo in tablet form for 4 weeks. In the active group, systolic blood pressure (SBP) decreased significantly as compared with the placebo group. In stratified analysis, however, this antihypertensive effect was not found in normotensive subjects. In addition, neither an acute or nor an excessive reduction in blood pressure nor clinically important adverse events were observed in this study. These findings suggest that intake of a 5-fold excess of tablets containing casein hydrolysate can lead to a mild improvement in hypertension without side effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Body Mass Index; Body Weight; Caseins; Double-Blind Method; Female; Humans; Hypertension; Japan; Male; Middle Aged; Oligopeptides; Peptidyl-Dipeptidase A; Placebos; Tablets

We describe a clinical trial to study the efficacy of a casein hydrolysate, prepared using an Aspergillus oryzae protease, containing the major angiotensin-I-converting enzyme inhibitory peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) in a single-blind, placebo-controlled study. A total of 131 volunteers with high-normal blood pressure and mild hypertension were randomly divided into four groups (n 32 or 33 in each group). Each volunteer was given two tablets containing four different dosages of VPP and IPP (VPP+IPP: 0, 1.8, 2.5 and 3.6 mg), daily for 6 weeks. A significant decrease in systolic blood pressure was observed at 6 weeks in the active group receiving 1.8 mg (P<0.01) VPP and IPP; in the active groups receiving either 2.5 mg or 3.6 mg, systolic blood pressure was decreased at both 3 weeks (P<0.05 and P<0.05) and 6 weeks (P<0.001 and P<0.0001) compared with systolic blood pressure measured before treatment. Changes in the systolic blood pressure after 6 weeks of treatment in the four groups were --1.7, --6.3, --6.7 and --10.1 mmHg, and these effects were dose dependent. In addition, a significant difference in systolic blood pressure between the placebo group and the VPP and IPP group receiving 3.6 mg was observed (P<0.001) by two-way ANOVA. The antihypertensive effect was greater in mildly hypertensive subjects (n 20 or 21 in each group) than in any of the other subjects. No significant change of diastolic blood pressure was observed for all the test groups, and no differences in diastolic blood pressure in the test sample groups compared with the placebo group were observed during the test period.

Topics: Administration, Oral; Adult; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Aspergillus oryzae; Blood Pressure; Body Mass Index; Body Weight; Caseins; Dietary Supplements; Female; Humans; Hypertension; Male; Oligopeptides; Single-Blind Method

The objective of these studies was to assess the toxicological potential of orally administered tripeptides in rats. The studies employed powdered L-valyl-L-prolyl-L-proline (VPP)- and L-isoleucyl-L-prolyl-L-proline (IPP)-containing test articles, including (1) powdered Lactobacillus helveticus-fermented milk (FM), (2) pasteurized casein hydrolysate (CH) generated by Aspergillus oryzae protease, and (3) synthesized VPP. All test articles were administered by oral gavage to male and female Sprague-Dawley rats. Specific goals of the single-dose and repeated-dose studies were to (1) identify doses that produce evidence of systemic and/or local (i.e., gastrointestinal) toxicity (e.g., lowest-observable-effect level [LOEL]); (2) estimate the maximally tolerated oral dose (MTD); and (3) identify specific target organs for toxicity of these tripeptides. Single doses of CH (2000 mg/kg), powdered FM (2000 or 4000 mg/kg), or VPP (40, 200, or 400 mg/kg) were administered 14 days prior to study termination. No treatment regimen caused either antemortem (gross observations, body weight, and food consumption parameters) or postmortem (necropsy) evidence of either systemic or local toxicity. In the repeated-dose study, powdered FM (0, 500, 1000, or 2000 mg/kg body weight [BW]/day) was administered by gastric gavage to male and female rats for 28 consecutive days. Antemortem evaluative parameters included gross observations, ophthalmic examinations, and clinical pathology (clinical chemistry, hematology, and urinalysis). Post mortem parameters included necropsy, determination of organ weights, and microscopic examination of major organs. There was neither in-life nor postmortem evidence that powdered FM administration caused physiological or toxicological changes. Under the conditions of these experiments, the single-dose LOEL of powdered FM, CH, and VPP were found to be greater than 4000, 2000, and 400 mg/kg, respectively. The results of the repeated-dose study do not support identification of a target organ for powdered FM toxicity. Similarly, there was no evidence to support establishment of either the LOEL or MTD; both being greater than 2000 mg/kg/day for up to 28 consecutive days.

Topics: Administration, Oral; Animals; Body Weight; Caseins; Cultured Milk Products; Dose-Response Relationship, Drug; Female; Hematocrit; Hemoglobins; Humans; Lactobacillus helveticus; Male; Oligopeptides; Organ Size; Powders; Rats; Rats, Sprague-Dawley; Sex Factors; Time Factors; Toxicity Tests; Urinalysis

The objective of these repeated-dose, 8-week studies was to assess the toxicological potential of a synthetic tripeptide, L-valyl-L-prolyl-L-proline (VPP), when administered to Charles River rats and Beagle dogs. Groups of 20 male and 20 female rats were fed powdered diets containing sufficient VPP to afford daily doses of 0, 2, 8, or 16 mg/kg body weight (BW)/day. Groups of five male and five female dogs were administered 0, 2, 8, or 16 mg/kg BW/day in hard gelatin capsules. Antemortem evaluative parameters for both species included grossly observable clinical signs, body weight and food consumption, clinical pathology (hematology, clinical chemistry, urinalysis), and ophthalmological examinations. Dogs also received electrocardiographic examinations. Postmortem evaluations in both species included complete necropsy, determination of major organ weights, and histopathological examination of specimens from approximately 50 organs and tissues. All rats and dogs survived to the scheduled termination of the studies and neither species exhibited evidence of VPP effects on appetite or body weight gain/maintenance. Ophthalmic examinations revealed occasional lens clouding in rats, but this occurred in all groups and was not attributable to VPP. Some clinical pathology parameters in both species were occasionally altered, but there was no evidence that this was dose-related. Electrocardiographic examinations in dogs revealed no VPP-associated changes. Mid- and high-dose male rats (but not females) had slightly reduced mean pituitary and kidney weight parameters, whereas mid- and high-dose females had slightly increased mean uterus:body weight ratios. There were no microscopic correlates for these minor changes. Ten percent to 20% of all female rats (but not males) exhibited corticomedullary mineralization of the kidney and gliosis of the optic nerve, and 10% to 20% of males (but not females) had thymic hemorrhage. Postmortem evaluations of dogs revealed no VPP-related effects on organ weights or either macro- or microscopic appearances of organs. The results of these studies provided no evidence of either local or systemic toxicity. Similarly, there was no evidence of neurotoxicity that might have been detected by the appearance of physical or behavioral changes during gross observations of animals. Although these results do not identify target organs for VPP toxicity, the no-observable-effect level and maximally tolerated dose are both greater than 16 mg/kg/day

Topics: Administration, Oral; Animals; Bilirubin; Blood Glucose; Body Weight; Calcium; Chemistry, Clinical; Corneal Opacity; Dogs; Dose-Response Relationship, Drug; Eating; Female; gamma-Glutamyltransferase; Hematology; Hemoglobins; Male; Monocytes; Oligopeptides; Organ Size; Ornithine Carbamoyltransferase; Rats; Sex Factors; Species Specificity; Specific Gravity; Time Factors; Toxicity Tests; Urinalysis

The objective of these studies was to assess the effects of the tripeptides, L-valyl-L-prolyl-L-proline (VPP) and L-isoleucyl-L-prolyl-L-proline (IPP), on reproductive capabilities of male and female rats. The specific goals of the experiments were (1) to determine the effects of orally administered tripeptides on (a) fertility and reproductive behavior in both sexes of rats, (b) embryo-fetal development in pregnant rats, and (c) pre- and postnatal development of rats exposed to tripeptides in utero and during lactation; and (2) to estimate the no-observable-adverse-effect doses of tripeptides in maternal and fetal rats. During the conduct of these classical segment I, II, and III studies, the test material was powdered Lactobacillus helveticus-fermented milk (FM), which contains the tripeptides, VPP and IPP. FM (0, 500, 1000 or 2000 mg/kg body weight [BW]/day--equivalent to 0, 0.8, 1.6, or 3.3 mg/kg BW/day of VPP plus IPP) was administered to males by oral gavage from 4 weeks prior to mating until sacrifice, and to females from 2 weeks prior to mating through day 20 of lactation. Evaluative parameters included monitoring grossly observable clinical signs; food consumption and body weight gains; mating behavior and fertility indices of both sexes; implantation and maintenance of embryos; sex ratio of live pups; fetal viability; incidences of external, visceral or skeletal variations; growth and behavioral development; as well as reproductive capabilities of F1 offspring exposed to FM during gestation and lactation. All animals were subjected to macroscopic examination at termination of their segment of the studies. Clinical signs, body weights, and food consumption were unaffected by administration of FM. During segment I, the test agent had no effect on estrus cycle, mating behavior, fertility index, or reproductive competence of either males or females. The results of segment II experiments revealed no effects of FM on postimplantation survival-loss, sex ratio or birth weights of live fetuses, and there was no evidence of treatment-associated developmental or teratological effects. During segment III, FM was without effect on pup viability, behavioral and sexual maturation, and reproductive capability of the F1 generation. Under the conditions of these experiments, the no-observable-adverse-effect level (NOAEL) of FM on reproductive performance in male and female rats is greater than 2000 mg/kg BW/day, the equivalent of 3.3 mg/kg BW/day of VPP plus IPP.

Topics: Animals; Animals, Newborn; Body Weight; Copulation; Cultured Milk Products; Dose-Response Relationship, Drug; Epididymis; Female; Fertility; Fetal Development; Kidney Pelvis; Lactobacillus helveticus; Male; Oligopeptides; Organ Size; Powders; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction; Sex Factors; Time Factors; Toxicity Tests