The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (PDF) – In 2003, the JNC identified prehypertension as a new risk category. Studies have shown that even slightly elevated blood pressure can lead to serious heart problems.

Meta-analysis of milk tripeptides on blood pressure – An independent organization conducts a meta-analysis of randomized controlled trials on the effectiveness of the lactotripeptides valyl-prolyl-proline (VPP) and isoleucyl-prolyl-proline (IPP). The meta-analysis concludes that milk-derived tripeptides have hypotensive effects in prehypertensive subjects. 

Scientific and Clinical Review – An overview of how AmealPeptide®, the key ingredient in ameal bp®, works as well as summaries of the studies that show its effectiveness.

Clinical studies of AmealPeptide® (lactotripeptides: VPP & IPP)

AmealPeptide®, the key ingredient in ameal bp®, has been evaluated in 14 double-blind and placebo-controlled studies. 

 

Efficacy Studies

A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects

American Journal of Clinical Nutrition, 64, 767-771 (1996)

A placebo-controlled study was conducted on the blood pressure of 30 elderly hypertensive patients, most of whom were taking antihypertensive medication. In the sour milk group, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased significantly 4 and 8 weeks after ingestion. No significant changes in blood pressure were observed in the placebo group.


The effect of sour milk on blood pressure in untreated hypertensive and normotensive subjects 
(article translated from Japanese to English by Calpis Co., Ltd.)

J Jpn Soc Clin Nutr, 23, 26-31 (2001)

18 untreated hypertension subjects and 26 normotensive subjects were divided into test group and placebo group. Sour milk containing tripeptides (VPP and IPP) was given to the test groups. Only in the hypertensive test group, SBP decreased significantly (12.1mmHg in 8 weeks). No effect was observed in the hypertensive placebo group, and normotensive test and placebo group.


Hypotensive effects of sour milk in subjects with mild or moderate hypertension 
(article translated from Japanese to English by Calpis Co., Ltd.)

J Jpn Soc Nutr Food Sci, 54, 347-354 (2001)

A placebo-controlled, double-blind study was conducted on 30 subjects with mild or moderate hypertension for 8 weeks to investigate the hypotensive effect of 160g sour milk drink. SBP and DBP were significantly decreased in the sour milk group. A significant difference in decrease of blood pressure was found between test group and placebo group.


Clinical effect of new sour milk drink on mild or moderate hypertensive subjects 
(article translated from Japanese to English by Calpis Co., Ltd.)

J New Remedies & Clinics, 51(1), 61-69 (2002)

Sour milk containing the tripeptides VPP and IPP was administered to 16 test subjects who had mild and moderate hypertension, along with 16 placebo subjects. Only for the test subjects, both SBP and DBP decreased significantly after 8 weeks of ingestion as compared to blood pressure prior to administration of the tripeptides. Also a significant difference was found in decrease in blood pressure between the two groups.


Randomized controlled trial of sour milk on blood pressure in borderline hypertensive men

Am J Hypertens, 17(8): 701-6 (2004)

A double-blind randomized controlled trial was done on 46 borderline hypertensive men who were not taking antihypertensive medication. Test group was administered sour milk containing the tripeptides VPP and IPP. After 2 weeks and 4 weeks, statistically significant blood pressure drop was seen for SBP only in the test group.


Hypotensive effects of the tablets containing "lactotripeptides (VPP, IPP)" 
(article translated from Japanese to English by Calpis Co., Ltd.)

J Nutr Food, 4(3), 51-61 (2001)

A placebo-controlled, double-blind study was conducted on 81 subjects with mild or moderate hypertension for 8 weeks to investigate hypotensive effects of the daily intake of tablets containing 5.3mg of tripeptides VPP and IPP. Significant decrease was seen for the test group, both for SBP and DBP. The decrease was also significantly greater than in the placebo group.


Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension

J. Am Coll Nutr., 24, 257-265 (2005)

40 subjects with high-normal (HN) blood pressure and 40 subjects with mild hypertension (MH) were tested in a randomized, placebo-controlled, double-blind study. Test group ingested 6 tablets/day containing the tripeptides VPP and IPP. In the test group, decrease of blood pressure (both SBP and DBP) was greater compared to placebo group, in both the HN group and the MH group.


Antihypertensive effects of liquid yogurt containing "lactotripeptides (VPP, IPP)" in mild hypertensive subjects 
(article translated from Japanese to English by Calpis Co., Ltd.)

J Nutr Food, 5(3), 55-66 (2002)

A placebo-controlled, double-blind study was conducted on mild hypertension subjects without treatment with drugs (33: placebo, 31: test) for 8 weeks. Samples used in this test were liquid yogurt containing the tripeptides VPP and IPP. Significant decrease was seen for the test group, both for SBP and DBP compared to the placebo group.


Effects of the liquid yogurts containing "lactotripeptide (VPP, IPP)" in high-normal blood pressure 
(article translated from Japanese to English by Calpis Co., Ltd.)

J Nutr Food, 7(1),123-137 (2004)

A placebo-controlled, double-blind study was conducted on high-normal blood pressure subjects (53: placebo, 53: test) for 12 weeks. Samples used in this test were liquid yogurt containing the tripeptides VPP and IPP. Significant decrease was seen for the test group, both for SBP and DBP compared to the placebo group.


Effect of casein hydrolyzate, prepared with protease derived from Aspergillus oryzae, on subjects with high-normal blood pressure or mild hypertension

J Med Food, 8(4), 423-430 (2005)

A placebo-controlled, double-blind study was conducted on high-normal blood pressure (n=104) and mild hypertension (n=40) subjects. Samples used in this test were VPP and IPP powder prepared from milk protein using Aspergillus oryzaeprotease, mixed into vegetable/fruits mix juice and pasteurized. After 12 weeks of treatment, both SBP and DBP of test group (n=72) decreased significantly compared to the placebo group (n=72).

Dose Response Studies

Antihypertensive effect of casein hydrolysate in a placebo-controlled study in subjects with high-normal blood pressure and mild-hypertension

British J Nutr., 94, 84-91 (2005)

A placebo-controlled, single-blinded study was conducted on high-normal blood pressure and mild-hypertension subjects. Samples used in this test were tablets containing 4 different dosages of VPP and IPP (VPP+IPP: 0, 1.8, 2.5, and 3.6mg) prepared from milk protein using an Aspergillus oryzae protease. After 6 weeks of treatment, dose dependent effect was seen. In addition, a significant difference in SBP between the placebo group and test group (3.6mg dosage group) was observed.

Safety (Human) Studies

Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension

J. Am Coll Nutr., 24, 257-265 (2005)

40 subjects with high-normal (HN) blood pressure and 40 subjects with mild hypertension (MH) were tested in a randomized, placebo-controlled, double-blind study. Test group ingested 6 tablets/day containing the tripeptides VPP and IPP. In the test group, decrease of blood pressure (both SBP and DBP) was greater compared to placebo group, in both the HN group and the MH group.


Safety evaluation of excessive intake of the tablet containing "lactotripeptides (VPP, IPP)" in healthy volunteers 
(article translated from Japanese to English by Calpis Co., Ltd.)

J Nutr Food, 4(4), 37-46 (2001)

A double-blind, comparative study was conducted to evaluate effects of excessive intake of tablet containing tripeptides (VPP and IPP) on healthy adult volunteers. 21 subjects ingested 6 tablets/day (7.8mg VPP and 4.5mg IPP) and compared with 22 placebo subjects. No marked changes were observed in blood pressure, pulse rate and blood serum variables.


Effect of large high intake of tablets containing "lactotripeptides (VPP, IPP)" on blood pressure, pulse rate and clinical parameters in healthy volunteers 
(article translated from Japanese to English by Calpis Co., Ltd.)

J Nutr Food, 4(3), 63-72 (2001)

A double-blind, comparative study was conducted to evaluate the effect of large intake of VPP/IPP (7 to 11 times than suggested dosage) contained in tablets. A group (10 healthy volunteers) ingested daily 14 tablets (37.3mg of tripeptides VPP and IPP) for seven days. No marked changes were observed in blood pressure, heart rate and blood serum variables.


Safety evaluation of excessive intake of drink containing "lactotripeptide (VPP, IPP)" in subjects with normal blood pressure to mild hypertension 
(article translated from Japanese to English by Calpis Co., Ltd.)

J Nutr Food, 7(4), 17-30 (2005)

A placebo-controlled, double-blind study was conducted to investigate the excessive intake (3 times more than suggested dosage) of vegetable/fruits mix juice with VPP/IPP powder, prepared from milk protein using Aspergillus oryzae protease. After 4 weeks of treatment, significant decrease was observed compared to initial value, but acute or excessive blood pressure reduction was not observed.


Safety evaluation of excessive intake of the tablet containing "lactotripeptide (VPP, IPP)" in subjects with normal blood pressure to mild hypertension 
(article translated from Japanese to English by Calpis Co., Ltd.)

Jpn Pharmacol & Ther., 34(10), 1107-1117 (2006)

A placebo-controlled, double-blind study was conducted to evaluate the excessive intake of the tablet containing tripeptides (VPP, IPP) on normal to mild hypertensive subjects. 27 subjects in test group ingested 20 tablets/day (5 times more than suggested dosage) and compared with 27 placebo subjects. While the systolic blood pressure was significantly reduced after 1 and 2 weeks in the test group, acute or excessive blood pressure reduction was not observed.

Safety (Animal) Studies

Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): I.
Executive summary

Int. J. Toxicol., 24(Suppl.4), p.1-3, 2005

This review, while containing some of the available pharmacology and efficacy information, deals primarily with the evaluation of data related to the safety of two tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline). This review consists of nine chapters, and this is the Executive Summary.


Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): II.
Introduction

Int. J. Toxicol., 24(Suppl.4), p.5-11, 2005

In 1997, products containing the two tripeptides VPP and IPP were approved Food for Specified Health Use (FOSHU) in Japan. Information on these two tripeptides are provided, including: physical/chemical properties, molecular weights, chemical structures, normal consumption in the diet, manufacturing information, regulatory approval in Japan, Japanese consumption of food containing enhanced levels of VPP plus IPP, and clinical data.


Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): III.
Single- and/or repeated-dose toxicities of tripeptides-containing Lactobacillus helveticus- fermented milk powder and casein hydrolysate in rats

Int. J. Toxicol., 24(Suppl.4), p.13-23, 2005

First published safety data on VPP and VPP plus IPP-containing substances is presented. Single-dose oral administration of 2000 mg/kg of casein hydrolysate powder, and 4000 mg/kg of powdered fermented milk, or 400 mg/kg of synthesized VPP caused no evidence of either systemic or local toxicity in male or female rats. It was concluded that the maximum tolerated dose (MTD) must be greater than 2,000 mg/kg BW/day.


Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): IV.
Assessment of the repeated-dose toxicological potential of synthesized L-valyl-L-prolyl-L-proline in male and female rats and dogs

Int. J. Toxicol., 24(Suppl.4), p.25-39, 2005

The oral administration of up to 16 mg/kg/day of VPP to male and female rats and dogs for 56 consecutive days produced no physical, biochemical, neurological or pathological evidence of treatment-associated changes. From these reports, no-observable-effect levels (NOEL) and MTD for VPP administered continuously for 8 weeks are >16 mg/kg/day. Based upon current projections of VPP incorporation into food, this equates to a margin of safety (MOS) of at least 160.


Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): V.
A 13-week toxicity study of tripeptide-containing casein hydrolysate in male and female rats

Int. J. Toxicol., 24(Suppl.4), p.41-59, 2005

Based on the results of this 91-day toxicity study, it is concluded that the NOEL is >1000 mg casein hydrolysate/kg BW/day (equivalent to 6.0 mg VPP plus IPP/kg BW/day) and the LOEL must be that level. The maximum tolerated oral dose in rats is also >1000 mg (equivalent to 6.0 mg of VPP plus IPP)/kg BW/day in both rat sexes and there was no evidence of specific target organs of toxicity for the powder in the rat.


Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): VI.
Effects of Lactobacillus helveticus -fermented milk powder on fertility and reproductive performance of rats

Int. J. Toxicol., 24(Suppl.4), p.61-89, 2005

Orally-administered 2000mg/kg BW/day of fermented milk powder (equivalent to 3.3mg/kg BW/day of VPP plus IPP), possesses little potential to 1) alter either the mating behavior or fertility of male or female Sprague-Dawley rats; 2) cause embryo or fetal toxicity; or 3) adversely affect pre- or postnatal development of offspring of dams administered powdered Fermented Milk during pregnancy and lactation. From this, the maximally tolerated dose (MTD) of powdered Fermented Milk is >2000 mg/kg BW/day (or >3.3 mg VPP plus IPP/kg BW/day) in both breeding/pregnant rats and the rat embryo-fetus.


Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): VII.
Micronucleus test of tripeptides-containing casein hydrolysate andLactobacillus helveticus fermented milk in rats and mice

Int. J. Toxicol., 24(Suppl.4), p.91-96, 2005

Administration of powdered casein hydrolysate 2000mg (containing 12mg VPP plus IPP) to male rats for 2 days, and single administration of powdered fermented milk 2000mg (containing 3.3mg VPP plus IPP) to male mice, failed to produce evidence of increased in vivo formation of either polychromatic erythrocytes (PCE) or micronucleated PCEs.


Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): VIII.
Assessment of cytotoxicity and clastogenicity of tripeptides-containing casein hydrolysate and Lactobacillus helveticus-fermented milk powders in chinese hamster lung cells

Int. J. Toxicol., 24(Suppl.4), p.97-105, 2005

Casein hydrolysate and fermented milk powders (containing VPP and IPP) were used as test articles (5000µg/mL of incubation medium) and cultured Chinese hamster lung cells as the test system, both with and without the rat hepatic metabolizing system (S9) and for short (6hr) and continuous (24hr) exposures, suggest that the test compounds and their constituents possess little or no demonstrable potential for the induction of cytotoxicity or clastogenic activity.


Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): IX.
Evaluation of the mutagenic potential of synthesized L-valyl-L-prolyl-L-proline in the Salmonella - Escherichia coli/microsome, incorporation assay

Int. J. Toxicol., 24(Suppl.4), p.107-113, 2005

Maximal concentrations of VPP (5,000 µg/plate) were tested for mutagenic potential to Salmonella TA98, TA100, TA1535, TQ1537, or E. coli WP2uvrA bacteria in the presence and absence of a mammalian microsomal metabolic activating mixture (S9). The results of the experiments revealed no treatment-associated changes in the incidence of revertant colonies in any bacterial strain tested. Therefore it is concluded, under the experimental conditions described, that there is no evidence that VPP possesses mutagenic potential.

 

* No adverse reactions such as dry cough, digestive tract symptoms or abnormal changes were observed for any of the tests we conducted.