Sobenin IA, Suprun IV, Orekhov AN
In: Atherosclerosis: risk factors, diagnosis, and treatment. Eds. GM Kostner, KM Kostner. Monduzzi Editore. 2002, pp. 305-308.

Introduction

We have shown recently that novel non-statin garlic-based time-released drug Allicor (INAT-Farma, Russia) possesses a wide range of effects on the most prominent cardiovascular risk factors: it lowers total and LDL cholesterol, increases HDL cholesterol, lowers systolic and diastolic blood pressure, activates fibrinolysis, inhibits platelet aggregation and improves glycemic control in diabetic patients. Due to such multifactor action, Allicor lowers estimated overall cardiovascular risk (1). Additionally, theoretical background exists to support the preposition that Allicor is a promising agent for the prevention and treatment of atherosclerosis. The results of in vitro and animal model studies demonstrated that garlic extract increases cholesterol ester hydrolase activity and inhibits acetyl coenzyme A:cholesterol acyl transferase, thus leading to the fall in intracellular cholesterol content (2). The inhibition of both cellular proliferating activity and the synthesis of connective tissue matrix components are also observed. Allicor possesses the significant antioxidant effect and lowers LDL susceptibility to oxidation (3). Additionally, we have determined that blood serum of patients after oral administration of Allicor decreases TNF-alpha, IL-1, HLA-DR and ICAM-1 expression in LPS-stimulated cultured human macrophages (unpublished data), thus affording ground for suggestion that long-term Allicor treatment can inhibit the development of inflammation and thus prevent atherosclerosis progression. So, to elucidate the possibility of direct antiatherosclerotic effects of Allicor, the double-blinded placebo-controlled randomized multicenter study was performed to monitor the effect of this non-statin drug on carotid atherosclerosis in men.

Materials and methods

Two hundred and six men with ultrasonographically revealed carotid atherosclerosis were randomized into two equal groups entirely comparable by age, serum lipid levels, blood pressure, smoking, family history, blood serum atherogenicity and intima-media thickness (IMT) of common carotid arteries. They received either Allicor, 300 mg daily, or placebo for two years, and the monitoring was provided every 6 months during follow-up. Ultrasonographic examination in B-mode followed by IMT measurement with Prosound program (R. Seltzer, USA) was used to monitor changes of IMT (4). Blood serum atherogenicity was assessed as the ability of patient’s serum to induce cholesterol accumulation in cultured mouse peritoneal macrophages (3). The expression of IL-1 and TNF-alpha in LPS-stimulated human cultured macrophages incubated in the presence of patient’s serum was used as the estimate of proinflammatory serum potential (5). Significance of differences was evaluated using SPSS 10.1.7 statistical program package (SPSS Inc., USA) and was assumed for P values <0.05.

Results

The significant difference in IMT changes between Allicor-treated (300 mg daily) and placebo groups was registered already after first 12 months of follow-up. Further regular Allicor administration resulted in the statistically significant decrease in intima-media thickening of common carotid arteries by 0.044 mm per two years of follow-up on an average, p<0.05 vs placebo group, where the slow growth by 0.029 mm per two years was observed (Fig. 1). Within Allicor-treated group, IMT significant reduction was observed in 51% patients vs 21% in placebo group (p<0.05). The further significant IMT increase was registered only in 18% patients in Allicor-treated group vs 53% in placebo group (p<0.05). Allicor treatment also resulted in the reduction of serum-induced expression of IL-1 and TNF-alpha in cultured human macrophages, thus demonstrating the anti-inflammatory effects of the drug. Moreover, this reduction correlated well with the changes in IMT (r=0.564, p<0.005 and r=0.483, p<0.02 for TNF-alpha and IL-1, respectively). On the other hand, IMT growth in placebo group was accompanied with the increase of both cytokines expression revealed in cell culture.

Conclusions

The results of this study demonstrate the antiatherosclerotic effects of novel garlic-based non-statin drug Allicor. The lipid-lowering effects observed during Allicor treatment may be regarded as negligible in comparison with potent statins, widely recommended for atherosclerosis prevention and treatment. So, the mechanisms of antiatherosclerotic action of drugs may differ significantly from the conventional idea of plasma cholesterol lowering that may be generally considered as indirect action via risk factor modification. As it was shown in cell culture tests, Allicor treatment prevents serum-induced intracellular cholesterol accumulation, thus providing the possible explanation for mechanism of atherosclerosis deceleration observed during ultrasound examination of common carotid arteries. On the other hand, we can assume that atherosclerosis progression is directly related to the development of inflammation, and the long-term treatment with drugs possessing anti-inflammatory activity like Allicor can prevent the growth of atherosclerotic lesions. On the whole, the obtained data can demonstrate the new insight into atherosclerosis prevention and treatment.

References

1. Sobenin IA, Orekhov AN. Positive results of primary prevention of atherosclerotic diseases. Ross. Cardiol. J. 1999.2:17-21.
2. Orekhov AN, Tertov VV. In vitro effect of garlic powder extract on lipid content in normal and atherosclerotic human aortic cells. Lipids 1997 32:1055-1060.
3. Orekhov AN, Tetrov VV, Sobenin IA, Pivovarova EM. Direct anti-atherosclerosis-related effects of garlic. Ann. Med. 1995 27:63-65.
4. Salonen R, Haapanen A, Salonen JT. Measurement of intima-media thickness of common carotid arteries with high-resolution B-mode ultrasonography: inter- and intra-observer variability. Ultrasound Med. Biol. 1991 17:225-230.
5. Rossi M, Whitcomb S, Lindermann R. Interleukin-1 beta and tumor necrosis factor-alpha production by human monocytes cultured with L-thyroxine and thyrocalcitonin: relation to severe root shortening. Am. J. Orthod. Dentofacial Orthop. 1996 110:399-404.

Abstract

The antiatherosclerotic and anti-inflammatory effects of garlic powder time-released tablets Allicor were studied in the double-blinded placebo-controlled randomized multicenter clinical study. Intima-media thickness of carotid arteries, blood serum atherogenicity and proinflammatory serum potential were monitored in men with ultrasonographically revealed carotid atherosclerosis. The results of two-year follow-up demonstrated that Allicor decreased intima-media thickening of common carotid arteries, reduced the serum-induced overexpression of IL-1 and TNF-alpha in cultured human macrophages, and lead to a significant reduction in blood serum atherogenicity that was revealed in cell culture tests. The ancillary antiatherosclerotic action of garlic-based non-statin drug Allicor allows the novel insight into atherosclerosis prevention and treatment.



Figure 1. The dynamics of IMT changes during two-year follow-up.
*, significant difference between Allicor-treated and placebo groups, p<0.05.