**3. Complementary effects of soy protein/peptide in combination with drugs**

#### **3.1 Effect of combined use with anti-hyperlipidaemic drugs**

The mechanism by which soy protein lowers cholesterol differs from that of statins and fibrates. Soy protein lowers serum cholesterol levels by acting as a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption by performing the same anion exchange reaction as the resin cholestyramine [68, 69].

Statins and fibrates are drugs developed to improve blood lipid levels. Statins are known as the most efficient agents for reducing plasma cholesterol. Statins target hepatocytes and inhibit 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase in cholesterol metabolism. Accordingly, statin and soy protein are expected to act additively or synergistically to decrease cholesterol levels. There are known serious side effects from statins, including muscle symptoms, rhabdomyolysis [secondary renal failure due to destruction of specific muscle tissue], peripheral neuropathy, myopathy, liver dysfunction, and thrombocytopenia [70–73]. Rhabdomyolysis often induces sudden kidney failure [74]. Fibrates, which are antagonists of peroxisome proliferator-activated receptor α [PPARα], are used in adjunct therapy for hypertriglyceridemia and are usually used in combination with statins. As fibrate-related side effects, the slight gastric region discomfort and myopathy [myalgia with increased creatinine phosphokinase] have been reported. In addition, increasing of the gallstones risk has been known by fibrates because of increasing of cholesterol in the bile duct. Use in combination of statins and fibrates is reported to even more raise the risk of rhabdomyolysis. So, combination use of these two agents is contraindicated in principle.

Nabiki et al. examined the effects of SPI on weight loss, markers of diabetes, and parameters of dyslipidaemia in obese diabetic patients by treated with statins and/or fibrates because of high levels of LDL cholesterol and triglycerides [75]. As a result, body weights of these patients decreased significantly by approximately 1 kg and their waist circumferences got thinner significantly by approximately 2 cm. Total cholesterol, triglyceride, LDL cholesterol, apolipoprotein B, and glycated hemoglobin levels of these patients decreased significantly, and HDL cholesterol levels increased significantly. In addition, a lipid metabolism-improving effect was also observed in patients who did not decrease weight. Therefore, it was suggested that the improving effect of lipid metabolism-related factors in these patients was not only due to weight loss but also a direct effect of soy protein. Use of soy protein may help to reduce the drug dose for dyslipidaemia. SPI is recommended for patients with mild dyslipidaemia prior to drug therapy or for maladaptive disease patients, such as those who have side effects from medications.

Combination prescription of fibrates and statins for patients with renal dysfunction and dyslipidaemia is contraindicated. Thus, physicians are unable to adequately treat lipid abnormalities for chronic kidney disease patients. It has been reported that when chronic kidney disease patients with dyslipidaemia ingested β-conglycinin, a major component of soy protein, for 3 months, triglyceride and LDL cholesterol levels improved. Renal function during the consumption period

of β-conglycinin showed a tendency to improve despite protein intake [76]. β-conglycinin may help improve lipid abnormalities in patients with renal dysfunction as a complementary medical food material without decreasing kidney function. Moreover, β-conglycinin may improve renal dysfunction as a direct and/or secondary effect of ameliorating lipid abnormalities.

#### **3.2 Concomitant effect with rheumatoid arthritis drug**

Rheumatoid arthritis is due to inflammation triggered by an immune response to autoantigens. Many of these patients have swelling and pain due to polyarticular arthritis. Their pain interferes with activities of daily living [ADLs], such as cleaning, washing, dressing, and undressing. These patients are anxious for more comfortable ADLs with reduced pain. The mechanisms of onset of rheumatoid arthritis have been reported in many studies. Based on these results, numerous new therapeutic agents have been developed.

As a specific case of improved inflammation, outpatients with rheumatoid arthritis consumed soy peptide with therapeutic drugs and the levels of IL-6 and IL-1β were significantly lower in the soy peptide group than the placebo group [77]. An increase in blood IL-6 levels is associated with extra-articular symptoms of rheumatoid arthritis, such as general malaise, loss of appetite, weight loss, and a slight fever. The Disease Activity Score 28 [DAS 28, objective assessment of rheumatoid arthritis disease activity by physicians] and the Clinical Disease Activity Index [CDAI, patient's own subjective indicator of rheumatoid arthritis disease activity] were calculated from the degree of ADLs' improvement, the severity of pain, and subjective symptoms recorded by visual analogue scale [VAS]. The DAS 28 score of the peptide group was markedly decreased, and the CDAI of the peptide group was significantly lower than that in the placebo group.

These effects on cytokines were also evident in a cell experiment using articular chondrocytes from patients with rheumatoid arthritis [78]. In this in vitro cell study, treatment with soy peptide significantly suppressed the mRNA levels of MMP-3 and ADAMTS-4 enhanced by IL-1β stimulation. This finding also suggests that soy peptides may prevent the degradation of articular cartilage.
