Nutraceutical Opportunities in Treatment of Diseases

Sickle cell disease (SCD) is a group of red blood cell abnormalities that are inherited. The disease results from mutation in the HBB (haemoglobin, beta) which helps in making the beta-globin protein. Heterozygotes produce a mixture of normal haemoglobin and sickle haemoglobin. Homozygotes only produce abnormal beta chains that make sickle haemoglobin, and this results in the clinical syndrome of sickle-cell disease. Sickle cell disease affects millions of people worldwide and affects people from several races and groups including Hispanics, South Asians, Caucasians from southern Europe, and people from Middle Eastern countries.

Key Points

• Altogether, over 100 million people worldwide carry the sickle cell trait.
• The disease is the most predominant monogenic disorder in humans worldwide and the single most common genetic disease in the United States, affecting approximately 100,000 Americans.
• The vast majority of SCD births occur in sub-Saharan Africa where at least 240,000 children are born with the disease every year
• SCD occurs in approximately 300,000 births annually. Nigeria, the Democratic Republic of Congo and India top the list of countries with SCD births.
•  An estimated 4,500 of these children are born in Kenya (Grosse et al. 2011).
• Worldwide, an approximate 50-90% of children born with SCD die undiagnosed before their fifth birthday.

Patients Living With Sickle Cell Disease Treatment Journey 

Once clinically diagnosed, common treatment of sickle cell disease involves patients initiating daily doses of folic acid tablets to boost their haemoglobin concentration levels even as there is not strong evidence of this. Antibiotic prophylaxis (penicillin V for those not allergic) is also sometimes administered to prevent against pneumococcal infection. Other treatments include use of Hydroxyurea, and blood and bone marrow transplant.

Presentation of sickle cell disease, or sickling, is precipitated by hypoxia, acidosis, dehydration and infection. Irreversibly sickled cells have a shortened survival (normal cells last 120 days) which may result in a number of acute syndromes termed crises and chronic organ damage. Vaso-occlusive crises (VOCs) are a type of several types of crises and presents with severe pain with somewhat uncommon objective clinical signs and are mostly identified through experience and subjective methods. In the US, VOCs lead to more than 197,000 Emergency Department (ED) visits and 356 million dollars spent on pain management every year.

Apart from the crises experienced by individuals with SCD, the disease has been shown to be associated with factors such as underweight and growth deficit, stunting, and wasting in children. Others include clinical variables such as haemoglobin concentration, disease progression, nutritional factors and the type of treatment implemented.

Crises from SCD are generally managed by aggressive intravenous rehydration, oxygen therapy, adequate analgesia (which often requires opiates) and antibiotics.

Despite the options available for the treatment of SCD, there is still a lack of reprieve from the crises experienced by SCD patients and the frequency of crises remains high among those who take the conventional drugs to prevent the crises, hence, morbidity and mortality rates of patients remains high. Thus, the United Nations General Assembly on 22nd December 2008, adopted a resolution recognising sickle cell anaemia as a public health problem.

Given opportunities that exist to help SCD patients better manage their disease, EvenFlo nutritional supplement was developed as treatment and prevention options. We did a study explored the efficacy of EvenFlo, a nutraceutical supplement, in conjunction with the traditional use of folic acid by conducting a clinical trial to test the effectiveness of combined use of these active agents in preventing the SCD crises, preventing and treating anaemia and increasing weight in the patients taking it and folic acid compared to those taking folic acid and placebo.

Statistics and Patterns

The information above and statistics are quoted from peer reviewed study findings as noted in the points below:

1. Sickle cell disease affects millions of people worldwide and affects people from several races and groups including Hispanics, South Asians, Caucasians from southern Europe, and people from Middle Eastern countries (American Society of Hematology [ASH], 2017; Piel, Hay, Gupta, Weatherall, & Williams, 2013).
2. Altogether, over 100 million people worldwide carry the sickle cell trait (American Society of Hematology [ASH], 2017; Piel, Hay, Gupta, Weatherall, & Williams, 2013).
3. The disease is the most predominant monogenic disorder in humans worldwide and the single most common genetic disease in the United States, affecting approximately 100,000 Americans (Centers for Disease Control and Prevention [CDC], 2019).
4. SCD occurs in approximately 300,000 births annually. Nigeria, the Democratic Republic of Congo and India top the list of countries with SCD births (Piel et al. 2013; Williams 2016).
5. The vast majority of SCD births occur in sub-Saharan Africa where at least 240,000 children are born with the disease every year (Piel et al. 2013; Williams 2016).
6. An estimated 4,500 of these children are born in Kenya (Grosse et al. 2011).
7. Worldwide, an approximate 50-90% of children born with SCD die undiagnosed before their 5th birthday (Grosse et al. 2011; Marsh et al. 2011; World Health Organization 2010).

EvenFlo Ingredients as a Nutraceutical With Medicinal Effects

EvenFlo is a nutritional supplement formulated to help manage SCD, particularly, the crises that SCD patients suffer and associated pain. The supplement was formulated to pro- mote bone marrow cells to enter the cell cycle and boost the production of red blood cells leading to significantly increased IL-3 secretion, and significantly inhibited IFN-γ secretion. This leads to increased haemoglobin concentration, and haematocrit (Guo & Wang, 2006; Hsu, Ho, & Lin, 1996; Liu et al. 2014). An earlier observation study conducted on EvenFlo appears to show a significant proportion of participants to have improved lifestyle in the form of improvement of appetite, anaemia, general health status, pain management, and weight management (Anicet et al. 2019).

The active components of EvenFlo that make it suitable of significantly limiting SCD crises by aiding red blood cell production leading to increased haemoglobin concentration and better weight management include atractylodes, codonopsis, corydalis, dong quai, jujube, licorice root or Szechuan lovage, poria, rehmannia root, salvia miltiorrhiza, and white peony.

Atractylodes are present in different forms including atractylenolactam, biatractylolide and atractylone. At- ractylenolactam exhibits anti-inflammatory activity and has anti-inflammatory, anticoagulation and gastrointestinal repair effects (Hoang le et al. 2016; Ji et al. 2016; Song et al. 2017; Tang et al. 2017). Biatractylolide has a neuroprotective effect on glutamate-induced injury (Zhu et al. 2017). Atractylone have anti-microbial and anti- inflammatory activities (Wu et al. 2020). Codonopsis has active ingredients that helps in the replenishment of vital energy deficiency, strengthening the immune system, improving poor gastrointestinal function, gastric ulcer and appetite and decreasing blood pressure (He et al. 2015).

Corydalis is used to treat pain, inflammation and gastro- intestinal dysfunctions. It significantly alleviates the mechanical allodynia (Lee, Son & Kim, 2010). Dong Quai, also known as Tang Kuei or Angelica sinensis has blood toning and nourishing effects attributed to its vitamin B12, folic acid, folinic acid, nicotinic acid, and biotin content (DeRosa & Cupp, 1997). The herb contains Z-ligustilide which has a calming effect on the nervous system, promoting relaxation and reducing pain. The herb also promotes haematopoiesis and can help increase blood volume after injury or surgery (Chao and Lin 2011; Deng et al. 2009).

Jujube is also known as Zizyphus Lotus. It is a tropical and subtropical plant used in nutrition, health and has antimicrobial, anti-inflammatory, hypoglycaemic, antioxidant, and immunomodulatory effects (Abdoul-Azize, 2016). Licorice root (also Szechuan lovage or ligusticum striatum) is a flowering plant in the carrot family which has have therapeutic properties and is used to treat a painful swelling of the joints. It has been shown to have triterpene saponins and flavonoids as its main bioactive compounds. This agent stimulates immune responses and activates antioxidant enzymes (Yang, Yuan, Ma, Zhou, & Liu, 2016).

Poria is an extract that can help increase the indexes of phagocyte, thymus, spleen, and promotes spleen antibody production, haemolytic activity, and delayed-type hypersensitivity (Chen, Zhang, & Cheung, 2010). Rehmannia Root is a blood refresher and has anti-oxidative, anti-inflammatory and anti-apoptotic effects. It helps to regulate deficient blood pat- terns such as anaemia, irregular menses, and uterine and post- partum bleeding (Huang et al. 2013; Yuan et al. 2018).

Salvia miltiorrhiza is a perennial plant with active ingredients that can cause coronary vasodilatation, suppress thromboxane formation, inhibit platelet adhesion and aggregation, and scavenge free radicals. It increases the activities of cata- lase, manganese superoxide dismutase, glutathione peroxidase, and coupled endothelial nitric oxide synthase. (Jiang et al. 2014; Yu et al. 2015).

White Peony (Paeonia sterniana) contains a unique glucoside called paeoniflorin, which calms nerves and alleviate spasm and pain (He & Dai, 2011). Working with other glucosides to make up total glucosides of peony (TGP), it has an anti-inflammatory effect and protects against oxidative dam- age (Wu, Pu, Yu & Li, 2015).

Results

A total of 120 SCD children were screened of which 70 children meeting the age requirement of 5 to 12 years were enrolled into the study. Thirty-five subjects were allocated into the treatment (envelope + standard of care) group and 35 into the control (standard of care) group. Thirty-two (91.4%) sub- jects in the treatment group and 29 (85.7%) in the control completed 6 months study follow-up and had complete data for analysis (Figure 1). All subjects were of African race. The baseline characteristics were similar between the two groups in terms of age, gender, weight, and haemoglobin level (Table 1).

Table 1: Demographic Characteristics

Figure 1. Profile plot of haemoglobin concentration

The primary outcomes data being the number of VOCs experienced by the subjects were compared between the two groups. With all 27 (93.1%) of the 29 subjects in the control group experiencing at least one form of crises by the end of the 6 months trial compared to none (0.0%) of the 32 subjects in the treatment group, there was a significant difference in the proportion of subjects that experienced at least one VOC (proportion difference = 0.931, 95% CI = 0.93 to 1.00, Z = 7.05, p < .001). This represents a 93.1% difference in the number of subjects that experienced crises. Further analysis of the crises experienced by the subjects in the control group during the trial shows that 2 (6.9%) experienced no crises, 10 (34.5%) experienced one crisis, 14 (48.3%) experienced two crises and 3 (10.3%) experienced three crises (Table 2).

Table 2: Vaso-Occlusive Crises Experienced During Clinical Trial.Data represent n (%)

Also, for weight, another secondary outcome variable, there were no outliers as assessed through the residuals. The assumption of normality was also partially violated with only the three subgroups of data from the intervention group satisfying the assumption (p > .05) while the three subgroups from the control violated it. There was homogeneity of variances (p > .05) and covariances (p > .001), as assessed by Levene's test of homogeneity of variances and Box's M test, respectively. Mauchly's test of sphericity showed that the assumption of sphericity was not met for the two-way interaction, χ²(2) = 6.17, p = .046. With this violation and the estimated value of epsilon greater than 0.75, we adopted the Huynh-Feldt correction based on the recommendations of Vieira (2017) and Girden (1992). The results of the interaction test showed that there was a statistically significant interaction between the treatment and time, on weight, F(1.90, 112.28) = 174.98, p < .001, partial η² = .748, ε = .952, thus, simple main effects were deter- mined. Data are mean ± standard error. The results showed that after 3 months, the intervention group had a mean weight (24.79 ± 0.87 Kg) statistically significantly higher than the control group (21.92 ± 0.91 Kg), F(1, 59) = 5.17, p = .027, partial η² = .081 (Figure 2). At the end of the 6 months trial, the intervention group had a mean weight of 26.63 ± 0.89 Kg, which was significantly higher than 21.79 ± 0.93Kg of the control group, F(1, 59) = 14.19, p < .001, partial η² = .194. Within the six months of trial, the intervention group increased their mean weight from the baseline by a mean of 4.47 Kg, 95% CI [4.02, 4.92] while the control group experienced a decrease (-1.05 Kg, 95% CI [-1.60, -0.51] in their mean weight in the same time period. Mean weight at the three time periods considered are shown in Table 3.

Table 3: Estimated Marginal Means for Weight and Haemoglobin. Data represent Mean ± SE

Figure 2. Profile plot of weight

EvenFlo is an effective agent in reducing the frequency of sickle cell disease crises as evidenced by a percentage difference of over 93.1% in the number of individuals that experience any form of crises during the trial. While no subject experienced an episode of VOC among the treatment group for the 6 months, 93.1% of the subjects in the control group experienced at least one crisis.

Evenflo is also effective in increasing the haemoglobin concentration of the blood for SCD patients. At the end of the 6 months trial period, the subjects in the intervention group had increased their haemoglobin concentration by a mean of 2.92 g/dl; this is significantly higher than 1.77 g/dl observed among those that took only folic acid. Similarly, the nutritional supplement saw the subjects in the intervention group increase their mean weight from the baseline by a mean of 4.47 Kg, while the control group experienced a decrease of 1.05 Kg in their mean weight during the trial period.

Overall, EvenFlo helps in the management of SCD by preventing VOCs due to SCD, increasing haemoglobin concentration and increasing weight; this is consistent with the findings of Anicet et al. (2019).

We imagine that EvenFlo provides a better alternative for SCD patients than some of the options previously available. For instance, hydroxyurea is commonly used to manage SCD. With the benefits derived from hydroxyurea also come the side effects of neutropenia, bone marrow suppression and mild peripheral blood cytopenia, elevation of hepatic enzymes, anorexia, nausea, vomiting and infertility (Agrawal, Patel, Shah, Nainiwal, & Trivedi, 2013). These side effects are conspicuously absent with EvenFlo.

Conclusion

The results from this randomised controlled trial showed that EvenFlo in addition to folic acid, is an effective agent in the management of SCD. Thus, we recommend the use of EvenFlo for the management of SCD patients as its effect would be useful in significantly limiting the onset of crises suffered by these individuals as well as boosting their haemoglobin concentration and weight indices possibly leading to improved quality of lives. We recommend to medics to embrace any promising nutraceutical products in the treatment of our patients, any nutraceutical that has potential to alleviate the suffering of the diseased, should be put through scientific clinical trials, findings put through peer review and products approved for usage under medical regulations like other pharmaceuticals.

We never know where the cure for the chronically borne diseases will come from, especially cancer.

Conflict of Interest

As, the author of this article, I have no conflict of interest in the manufacturing, sale or distribution of this nutraceutical. The manufacturer of the EvenFlo nutraceutical sponsored the clinical trial.