Anti-inflammatory supplement effect on diastolic pressure in healthcare workers: a single arm cohort study

Luis Giovanni Rosales Pichardo¹, José Anaya Herrera², Rosaura Pérez Martínez², Hugo Mendieta Zerón^1,2

¹ Faculty of Medicine, Autonomous University of the State of Mexico (UAEMéx). Av Paseo Tollocan, Calle Jesús Carranza, Moderna de la Cruz, 50180 Toluca, Mexico
² “Mónica Pretelini Sáenz” Maternal-Perinatal Hospital. Paseo Tollocan 201 Poniente, Col. Universidad, C.P. 50010, Toluca, Mexico

Corresponding Author:
Hugo Mendieta Zerón, MD. PhD.
Email: [email protected]

DOAJ: 21355d84313342bdbe564972c4b17810
DOI: https://doi.org/10.48107/CMJ.2024.09.001
Published Online: September 21, 2024

Copyright: This is an open-access article under the terms of the Creative Commons Attribution License which permits use, distribution, and reproduction in any medium, provided the original work is properly cited.

©2024 The Authors. Caribbean Medical Journal published by Trinidad & Tobago Medical Association

KEYWORDS: antioxidants, healthcare workers, diastolic blood pressure

ABSTRACT
Objective: Belage®, an anti-inflammatory supplement made with extracts of rosemary and olive, stimulates and increases the activity of the two main antioxidant enzymes: superoxide dismutase (SOD) and glutathione peroxidase (GPX). These actions may help to control blood pressure. The main objective of this research was to determine if there was any change in the anthropometric and blood pressure measurements in health personnel when taking Belage®.

Methods: This prospective and interventional study was performed at the “Mónica Pretelini Sáenz” Maternal-Perinatal Hospital (HMPMPS), Toluca, Mexico; from July to December 2020. Health workers > 18 years were prescribed Belage® at a rate of 3 g dissolved in 500 ml of water per day. The following variables were measured at baseline and every month for three months: age (years), weight (kg), height (m), systolic blood pressure (SBP) (mmHg), diastolic blood pressure (DBP) (mmHg) and mean blood pressure (MBP) (mmHg). Using the paired t-test, monthly measurements of these variables were compared to the baseline measurements.

Results: Eighty-two workers completed the three-month follow-up. Of the total study participants, 13 (15.86%) were men and 69 (84.14%) were women. Significant changes were observed after one month of treatment in Diastolic Blood Pressure (DBP) (P =0.0008), Mean Blood Pressure (MBP) (P =0.00012), Systolic Blood Pressure (SBP) (P = 0.00191), and Body Mass Index (P = 0.0117). Significant changes persisted until the end of the follow-up period.

Conclusion: The reductions in blood pressure seen with Belage® use in this study warrant future controlled trials.

INTRODUCTION
Under physiological conditions, oxidative stress is unavoidable. Due to continuous aerobic metabolism, oxidative species are formed and later degraded by endogenous antioxidants (usually enzymes), maintaining cellular homeostasis. These oxidative substances include reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂) and ozone (O₃); and free radicals such as superoxide (O^2-), hydroxyl (OH^–), peroxyl (RO₂) and hydroperoxyl (HO₂-). To a lesser extent, reactive nitrogen species (RNS) such as nitric oxide (NO), nitrogen dioxide (NO₂), and nitrous acid (HNO₂) are also produced.

In small amounts, oxidative substances, especially ROS, have beneficial effects on cells, mainly linked to immune function.^(1–3) However, in large amounts, these oxidative substances can lead to endothelial dysfunction, which can cause damage to organs and tissues and even lead to cognitive damage.

The human body has an efficient antioxidant system aimed at reducing the harmful effects of oxidative substances, DNA mutations, malignant transformations as well as other parameters of cellular damage.⁴ Among the major enzyme systems that exert this function superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase are key contributors. When there is a functional decline of this system, or an excess of oxidizing species exceeds its neutralizing capacity, oxidative stress results. According to Sies, oxidative stress is defined as “the disturbance in the balance between pro-oxidants and antioxidants, in favor of pro-oxidants.”⁵

Inflammation and oxidative stress, contribute to the pathogenesis of diseases such as Parkinson’s disease, aging, Alzheimer’s disease, the carcinogenic process, diabetes and other chronic degenerative diseases³ by inducing changes in the cells’ biochemistry, altering the structure and function of proteins, lipids, and DNA.¹

Immune cells interact with antigens and produce a complex response, including inflammation. ROS and RNS also increase cytokines and chemokines triggering inflammation. When inflammation becomes chronic, the oxidative stress intensifies and cellular damage increases. It is important to highlight that oxidative stress, inflammation, and free radicals are components of the same sequence of cellular events and they augment each other in a feedback process.^(2,6)

Another disease whose pathogenesis includes these mechanisms is obesity. An escalating global epidemic of overweight and obesity – “globesity” – is taking over many parts of the world, and it is thought that in the next few years, if immediate action is not taken, millions will suffer from an array of serious health disorders.⁷ The association between inflammation and obesity (the latter being a low-intensity chronic inflammatory state) is usually associated with other pathologies, such as diabetes mellitus and arterial hypertension. In obesity, there is an energy imbalance that manifests itself as the accumulation of adipose tissue which later leads to alterations in the immune response that induce the release of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL6), and C-reactive protein (CRP). ^(8,7)

A high prevalence of chronic degenerative diseases (e.g. diabetes, obesity, and hypertension) exists in Mexico. According to data from the Mexican National Health and Nutrition Survey 2018 (ENSANUT 2018), the percentage of adults aged 20 years and over, with overweight and obesity (O&O) is 75.2% (39.1% overweight and 36.1% obesity).⁹  High prevalences (61%) of O&O were noted in healthcare workers with resultant chronic non-communicable diseases.¹⁰ Other studies yielded similar results. ^(11,12)

In Mexico, the main cause of mortality is cardiovascular disease (CVD), with an estimated mortality rate of 134 deaths per 100,000 people.¹³ Hypertension is the most important risk factor for the development of CVD,¹⁴ but up to 55% of people with this disease are often undiagnosed as they are often asymptomatic.¹⁵ An underlying chronic disease can worsen health outcomes in an acute infection such as COVID-19.¹⁶

It is well known that oxidative stress plays a prominent role in several chronic diseases. ^(17,18)  Hence, countless antioxidant products have been proposed. One of these is the Belage®, which was the result of 15 years of research in fermentation technologies, containing an active ingredient with high bioaccessibility: Orisod Enzyme III. Belage® stimulates and increases the activity of the two main antioxidant enzymes: SOD and GPX, which play a crucial role in protecting cells against free radical damage. The ingredients of this supplement are cornstarch, citric acid, potassium citrate, Orisod® [olive extract (Olea europaea l.), Rosemary extract (Rosmarinus officinalis l.)], natural flavors, tricalcium phosphate, sucralose, and natural colorants (chlorophyll).¹⁹ It is hypothesized that the administration of this substance may improve the antioxidant function, controlling the inflammatory cascade. The main objective of this research was to determine if there was any change in the anthropometric and blood pressure measurements in health personnel when taking Belage®.

METHODS
Study design and setting
A longitudinal, prospective, and interventional study was conducted from July to December 2020. The investigation was carried out at the “Mónica Pretelini Sáenz” Maternal-Perinatal Hospital (HMPMPS), Health Institute of the State of Mexico (ISEM), Toluca, Mexico.

Study participants and recruitment
All hospital workers were invited to participate in the study. The inclusion criteria were health workers of legal age (> 18 years). People with chronic diseases were included in the study. Those workers with a history of COVID-19 disease were excluded as chronic complications could be severe and unknown; as well as those lost to follow-up.

Strict follow-up was maintained with visits to their services to remind them about taking their supplements and the dates of their monthly check-ups. They were also reminded of this through emails, WhatsApp, or phone calls.

Intervention: All participants were prescribed Belage® (provided by Sanki-Mayor, Japan), at a rate of 3 g (usual prepackaged commercial presentation) dissolved in 500 ml of water freely ingested throughout the day. Adherence to management was verified with supervision in the same workplace through a reminder process to maintain the treatment. To carry out this action, the researchers divided the participating volunteers to remind them of messages of the project’s instructions. In addition, weekly monitoring of the consumption of the sachets was carried out, only asking how many sachets had been consumed of the 30 that were given to each participant monthly.  Adequate compliance was considered if there were a maximum of two forgettings to take the sachet per month. Adverse effects were also monitored and recorded.

Baseline and follow-up measurements
The following variables were measured at baseline and then every month for three months: age (years), weight (kg), height (m), systolic blood pressure (SBP) (mmHg), diastolic blood pressure (DBP) (mmHg), mean blood pressure (MBP) (mmHg). Weight (kg) and height (m) were measured using a mechanical column scale (SECA 220) and blood pressure was measured with an automatic sphygmomanometer (Citizen). BMI was calculated as mass in kg divided by height in meters squared (kg/m²).

Sample size
The following formula was used for population calculations²⁰:

Where Zα = 1.96, S (standard deviation of diastolic blood pressure) = 8, d (error in diastolic blood pressure) = 1.25, giving a n₀ = 80.3 health workers. 

Statistical analysis
Data was collated and coded, and initial analysis was performed in a Microsoft Excel worksheet, to obtain descriptive statistics – the mean, standard deviation (SD), minimum and maximum values of each quantitative variable. To compare the baseline and final data, the paired t-test was applied, first verifying the distribution of the variables with the Kolmogorov test. P-values less than 0.05 were considered statistically significant. Statistical analyses were performed using the Social Science Statistics online software.²¹

RESULTS
During the study period, there were 1,280 health workers in the Hospital on all shifts. All were invited to participate. Of these 410 expressed interest in participating, 366 attended the first explanatory appointment and 120 enrolled in the study.

Of these 120 participants, 12 did not adhere to treatment protocol in the first month, 8 in the second month, and 7 in the third month, leaving 87 participants. However, five participants with severe COVID-19 had to be excluded from the study.  Eighty-two (82) subjects completed the three months of follow-up, while 38 (31.6%) were excluded.

Table 1 shows the clinical characteristics of the 82 participants who completed the three months of follow-up. It shows the mean and standard deviation of each variable; and the changes recorded over the following months. Of the 82 participants, 13 (15.86%) were men and 69 (84.14%) were women.  The basal value of BMI was 27.5 ± 4.5 kg/m², SBP: 121.3 ± 14.8 mmHg, DBP: 79.1 ± 8.9 mmHg, and MBP 93.2 ± 9.9 mmHg. After three months, their values were 27.0 ± 4.3 kg/m², 111.9 ± 11.8 mmHg, 70.3 ± 7.6 mmHg and 84.2 ± 6.0 mmHg respectively.  Of note, the differences between baseline versus 2 months and baseline versus 3 months were similar. Table 2 represents each of the variables studied distributed by gender. 

Table 1. Clinical characteristics of healthcare workers (N = 82, 13 men and 69 women)*

* Each variable is expressed in mean ± 1 standard deviation.
BMI: Body Mass Index, DBP: Diastolic Blood Pressure, MBP: Mean Blood Pressure, SBP: Systolic Blood Pressure. a: between basal value and month 1, b: between basal value and month 2, c: between basal value and month 3.

Table 2. Distribution of variables by gender*

* Each variable is expressed in mean ± 1 standard deviation.
BMI: Body Mass Index, DBP: Diastolic Blood Pressure, MBP: Mean Blood Pressure, SBP: Systolic Blood Pressure.

DISCUSSION
Diet has a profound effect on chronic diseases such as cardiovascular complications, diabetes mellitus, hypertension, etc., and the scientific evidence suggests that the use of antioxidants should be limited only to cases where oxidative stress has been confirmed.²²

At present, several natural products have been tested against chronic diseases. For example, researchers at the Isfahan University of Medical Sciences in Iran assessed the effect of an antioxidant substance on liver function, blood pressure, and anti-oxidative status in patients with fatty liver. They conducted a double-blind, randomized study where they administered Hibiscus sabdariffa (sour tea) capsules for eight weeks. Interestingly, there was a decrease in oxidative stress, SBP, and DBP levels, among other beneficial effects.²³

Other similar studies have shown the effectiveness of the administration of an antioxidant substance to achieve decreased blood pressure as well as to reduce the oxidative stress of the individual. This was shown in a recent study that indicates that the use of Moringa oleifera extract has a positive effect on blood pressure levels by improving the production of nitric oxide, which is a powerful vasodilator. Similarly, the use of capsinoids reduced the DBP, while the administration of fermented red pepper paste produced similar effects on SBP. ^(24,25)

Among the components of Belage®, Olea europaea l, and Rosmarinus officinalis were found to be cardioprotective²⁶ and to lower blood pressure.²⁷ One previous study among pregnant women in the second trimester that used (N = 144) or did not use (N = 99) this product, found significant statistical differences in the DBP (P = 0.002) and MBP (P = 0.001) (N = 144) after one month of treatment²⁸, with these measures being lower in the experimental group. The current study has shown that Belage® use produces significant changes in DBP, MBP, SBP, and BMI in a short time frame.  The similar differences between baseline vs. 2 months and baseline vs. 3 months could be attributed to a plateau effect that has been described in other clinical approaches.²⁹ Specifically, the effect of a reduction of approximately 10 mmHg in diastolic pressure on health status is not clear, but there is evidence of the importance of this parameter when it is correlated with renal function in patients with type 2 diabetes mellitus.³⁰ Of note, BMI was reduced throughout the administration of the supplement.

Several studies have indicated that the administration of antioxidants may have beneficial effects on overweight and obese patients by improving the lipid profile and, in some cases, achieving a decrease in body weight.³¹ For example, the administration of L-carnitine has a significant effect in reducing body weight and blood pressure, in addition to reducing triglyceride and blood glucose levels.³² Based on this information, we found it necessary to further explore the effects of Belage® on these variables. As far as the authors are aware, and after searching different article bases such as Pubmed, Scopus, Redalyc, Scielo and Google Scholar, this is the first study that suggests a beneficial effect on BMI when using Belage®.

It can be concluded that supplementation with Belage® 3 g daily dissolved in 500 ml of water for 12 weeks is beneficial in obtaining significant reductions in DBP, MBP SBP, and BMI. Weight reduction would lead to blood pressure reduction and possibly more biochemical benefits.

However, several limitations should be considered when interpreting our results. The percentage of cases that were lost may have affected the results and therefore the generalization of the changes in the variables must be taken with caution. It was not a comparative study with a control group, which may introduce bias and confounding. Analysis of the participant’s diet was not done which could have been a confounder.  Future longitudinal studies could be set up to see how long the changes in blood pressure and BMI would be sustained. A randomized control trial could also be set up to compare the effects of Belage® use against a group of controls.

CONCLUSION
The reductions in blood pressure and BMI seen with Belage® use in this study warrant future controlled trials to further evaluate its effects.

Acknowledgement: The authors sincerely thank Blanca Janeth Hernández Quiroz, Arisai Durán Tejada, Yomara Lizbeth Martínez Morales, Ofelia Roxana Sotelo Martínez, José Antonio Mendoza López, Yave Anzaldo Gallegos, Nancy Santamaría Benhumea and Martha Yoatzin Costilla Martínez for their help in obtaining the participants’ data.
Ethical approval statement: The protocol was approved by the Research Ethics Committee of the HMPMPS with the following registration number: 2020-11-709. This research is in adherence with the ethical and legal standards of Mexico. Informed consent was obtained from all participants.
Financial disclosure or funding: Belage® was provided by Sanki-Mayor, Japan.
Conflict of interest: There were no conflicts of interest to disclose.
Informed consent: Obtained.
Author contributions: Authors’ contribution: JAH and HMZ contributed to the study’s conception and design. LGRP and RPM contributed to the material preparation and data collection. Data analysis was performed by HMZ. The first draft of the manuscript was written by HMZ and LGRP. All authors read and approved the final manuscript.

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