Abstract: Diabetes mellitus is one of the common diseases in China, and chronic vascular complications of diabetes mellitus are a great threat to the life and quality of life of patients. Microcirculatory disorders are an important pathological and physiological basis for chronic complications of diabetes, and prostilbestrol, as a highly active bioactive substance, can improve microcirculation, effectively alleviate the symptoms of chronic complications of diabetes and delay their development. Wei Jing, Endocrine Specialist, Jinan Hospital of Traditional Chinese Medicine
Keywords: Prostil, diabetes mellitus, chronic complications
Diabetes mellitus is one of the common diseases in China at present. According to the epidemiological survey in 2008, its prevalence has reached 9.7% and 15.5% of people with abnormal glucose tolerance. The harm of diabetes is mainly manifested in the damage to large blood vessels and microvessels caused by its damage to vascular endothelium, and the chronic vascular complications of diabetes are a great threat to patients’ lives and quality of life. Therefore, the treatment of diabetes is not only limited to lowering blood glucose, but also preventing and delaying the occurrence and development of macrovascular or microvascular complications, and reducing the disability and death rate of patients. Prostilbestrol (prostaglandin E1) is an extremely active bioactive substance that not only has a significant vasodilating effect, but also inhibits platelet aggregation, reduces blood viscosity and red blood cell aggregation, prevents atherogenic lipid plaque formation and improves nerve damage. Microcirculatory disorders are an important pathological and physiological basis for chronic diabetic complications, so prostilbestrol can effectively relieve the symptoms of chronic diabetic complications and slow down their progression. The application of prostilbestrol in chronic complications of diabetes mellitus is described as follows.
1. Large vessel lesions.
1.1. Coronary heart disease. We believe that diabetes mellitus and cardiovascular disease are manifestations of the same pathophysiological process in different tissues, and diabetes mellitus is an equivocal condition of coronary heart disease. Liu Qiuli et al [1] randomly divided 80 patients with diabetes mellitus combined with coronary heart disease into 40 cases each in the observation group and the control group, and under the comprehensive treatment of all patients with effective hypoglycemia and hypotension, the observation group was also applied prostilbestrol injection 200ug into 0.9% sodium chloride injection 250ml intravenously once a day for a total of 10 days. The patients in the observation group had an efficiency of 90% in the improvement of the main symptoms and 62.5% in the improvement of the electrocardiogram after treatment. Zhang Yan et al [2] examined the blood rheological indexes in 86 patients with type 2 diabetes (53 patients with combined coronary heart disease and 33 patients with diabetes alone), and the patients with type 2 diabetes combined with coronary heart disease were treated with prostaglandin E1 to observe the changes of their blood rheology. The results showed that compared with the control group, the whole blood high cut viscosity, whole blood low cut viscosity, plasma viscosity, fibrinogen, erythrocyte aggregation index and platelet aggregation rate of type 2 diabetic patients were significantly higher (P < 0.05) and the erythrocyte deformation index was significantly lower (P < 0.05), among which the changes were more significant in the group with diabetes mellitus combined with coronary heart disease (P < 0.05). Prostaglandin E1 significantly reduced blood viscosity and platelet aggregation rate in patients with diabetes mellitus combined with coronary artery disease (P < 0.05). Yang Yi and Zhu Lei [3] randomly divided 75 patients with type 2 diabetes mellitus combined with coronary heart disease into 40 cases in the observation group and 35 cases in the control group. Both groups were given prostaglandin 200ug into 0.9% sodium chloride injection intravenously once a day for 14 days under the premise of conventional hypoglycemic and antihypertensive treatment; the control group was given isosorbide mononitrate 20mg twice a day for 14 days. The results showed that total cholesterol, triglyceride, HDL, LDL and all blood rheological indexes in the observation group were significantly improved, and all indexes in the observation group were significantly better than those in the control group, except for erythrocyte pressure volume. It can be seen that patients with diabetes mellitus combined with coronary artery disease have obvious lipid and blood rheology abnormalities, and the application of prostaglandin can significantly reduce the patients' lipid levels and improve the blood rheology indexes.
1.2. Cerebrovascular lesions. Diabetes mellitus is one of the most risk factors for ischemic stroke. The reasons for this are related to increased blood viscosity, accelerated erythrocyte sedimentation rate, increased fibrinogen and enhanced platelet adhesion and aggregation in diabetic patients. Stroke complicated by diabetes mellitus is characterized by a high number of small and medium-sized infarcts and multiple lesions. Li Xianhou et al [4] randomly divided 64 patients with diabetic cerebral infarction into 2 groups; both groups were administered within 3 days of onset and treated for 15 days as a course of treatment. In the treatment group, saline plus prostaglandin microsphere carrier preparation 20 mg was administered intravenously on days 1-8, and saline plus prostaglandin microsphere carrier preparation 10 mg was administered intravenously on days 9-15; in the control group, saline plus hemosiderin 0.4 was administered intravenously, and medication to restore neurological function was also applied to support treatment. The total effective rate of the treatment group was 93.7%, which was significantly better than that of the control group (P<0.05). Li Hong et al [5] randomly divided 48 patients with type 2 diabetes mellitus combined with lacunar cerebral infarction into conventional group and prostilbestrol group. The prostilbestrol group was treated with prostilbestrol 20ug intravenous drip daily on the basis of conventional treatment, and after 14 days of application, the changes of blood rheological indexes and fasting blood glucose, 2-hour postprandial blood glucose, total cholesterol, triglycerides and other indexes were examined before and after treatment in the two groups. The results showed that the whole blood viscosity, plasma specific viscosity, plasma fibrinogen concentration and platelet aggregation rate in the prostil group were significantly lower than those in the conventional treatment group, indicating that prostil had different degrees of improvement on the blood rheology of patients with type 2 diabetes combined with lacunar cerebral infarction.
1.3. Peripheral macrovascular atherosclerosis. Diabetic peripheral large-vessel atherosclerosis mainly refers to lower limb atherosclerosis occurring on the basis of diabetes mellitus, causing ischemia in the distal tissues of the lower limbs, characterized by a wider and more distal distribution of lesions, and the affected vessels are often multi-site and multi-segmental with microangiopathy. Wang Aihong et al [6] randomly divided 204 patients with type 2 diabetes mellitus combined with lower extremity arterial occlusive disease into 2 groups, group 1 (103 patients) was given Kaiser (Prostil injection) 10ug IV drip daily, group 1 (101 patients) was given Prostil 10ug IV drip daily, and both groups were given the drug for 20 days, and the patients’ lower extremity pain was observed, and the patients’ pain-free walking distance, and the maximum walking distance that could tolerate The maximum pain-free walking distance and pain-tolerant walking distance as well as the ankle-brachial blood pressure index (ABI) were measured. The results showed that prostilbestrol significantly improved the pain-free walking distance, significantly improved the symptoms of intermittent claudication, increased the maximum walking distance, significantly decreased the pain score, and increased the ABI values. Prostil dilates peripheral blood vessels, reduces peripheral arterial vascular resistance, improves arterial blood flow in the lower extremities, and is able to act specifically on arteries with stenosis and plaque. The main mechanisms are 1) increasing the level of camp in cardiomyocytes by excitation of adenylate cyclase, activation of protein kinase, and relaxation of smooth muscle, thus dilating coronary arteries, peripheral arteries, and veins; 2) inhibition of platelet aggregation by phosphorylation of platelet granule membrane proteins and reduction of intracytoplasmic calcium ion concentration; and 3) reduction of its potent pro-platelet aggregation by inhibition of platelet synthesis of txa2 effect [7].
2. microangiopathy. In diabetic patients, plasma glycated protein concentration is increased, which puts the blood in a hypercoagulable state; in addition, the deformability of erythrocytes is reduced in diabetes, and endothelial cell damage results in reduced prostacyclin (PGI2) synthesis. These causes can cause microvascular occlusion and microthrombosis, which play an important role in the occurrence of microangiopathy.
2.1. Diabetic nephropathy. Diabetic nephropathy is the most common and serious microvascular complication of diabetes, and one of the most important causes of death and disability in diabetes, and the primary disease leading to end-stage renal failure. Elderly diabetic patients are mostly accompanied by hypertension and atherosclerosis, and most of them have insidious onset and long duration of disease, so their nephropathy is not only high in incidence, but also serious and fast progressing. Liu Jifeng [8] randomly divided 66 patients with early diabetic nephropathy into treatment and control groups. On top of the same glucose-lowering and antihypertensive basic treatment, the treatment group added prostilbestrol 10ug intravenous push once a day for 14 days, and the results showed that the 24-hour urine microalbumin quantification in the treatment group decreased significantly compared with that before treatment, and the difference was statistically significant. Cao Xueying et al [9] randomly divided 42 patients with diabetic nephropathy into 2 groups, in addition to conventional treatments such as hypoglycemia and hypotension, the treatment group was given prostaglandin 10ug in 0.9% sodium chloride injection 100ml intravenously, and the control group was given oral dipyridamole, both applied for 2 weeks, and the patients were observed for 24-hour urine protein quantification, plasma albumin (ALB), cholesterol, blood creatinine, blood Urea nitrogen, endogenous creatinine clearance and adverse effects. The results showed that prostilbestrol treatment in patients with diabetic nephropathy could rapidly reduce proteinuria, significantly increase ALB, significantly decrease blood creatinine and blood urea nitrogen, significantly decrease endogenous creatinine clearance, and have few side effects and adverse reactions. Zhang blow [10] divided 81 patients with diabetic nephropathy into 45 cases in the treatment group and 36 cases in the control group, and the 2 groups were further divided into 3 subgroups: the early nephropathy group, the clinical stage normal renal function group, and the clinical stage renal insufficiency group. On the basis of blood glucose, blood pressure and lipid control in all patients, the treatment group was given prostilbestrol 10ug intravenous push once a day for 14 days, and the results showed that the total urinary protein and urinary albumin were significantly reduced in the treatment group compared with the control group. Zhang et al [11] randomly divided 84 patients with diabetic nephropathy into 2 groups, both groups received conventional treatments such as hypoglycemia, hypotension, lipid regulation, anticoagulation, etc. The experimental group was given prostaglandin E1 200ug in saline 250ml intravenously once a day for 10 days as a course of treatment, and the results showed that prostaglandin E1 treatment for diabetic nephropathy could effectively reduce proteinuria and improve renal function. Zhang Huijuan et al [12] randomly divided 82 patients with diabetic nephropathy into 42 cases in the experimental group and 40 cases in the control group, both groups were given a low protein diet, insulin subcutaneous injection, and antihypertensive drugs of ACEI or ARB class, the experimental group applied prostaglandin E1 10ug into saline 100ml intravenously once a day for 2 weeks, the control group applied thromboxane 450mg into In the control group, 450mg of thromboxane was added to 250ml of saline and injected intravenously once a day for 2 weeks. Blood pressure, blood routine, urine routine, fasting blood sugar, 24h urine albumin quantification, blood creatinine, urea nitrogen, liver function and blood lipid were observed before and after treatment in the two groups. The results showed that urine protein decreased in both the test and control groups after treatment, and the decrease in urine protein was more obvious in the test group, indicating that the effect of prostaglandin E1 adjuvant treatment for diabetic nephropathy was better than conventional treatment. Mou Yarou [13] observed through clinical studies and animal experiments and concluded that 1) prostaglandin E1 significantly reduced urinary protein and urinary albumin excretion in patients with diabetic nephropathy and was more effective in early diabetic nephropathy than in late diabetic nephropathy. 2) The effect of prostaglandin E1 in reversing or reducing diabetic nephropathy may be related to its ability to reduce plasma and renal cortical ET-1 and Ang II levels and to reduce renal tubular cell apoptosis. The lipid microsphere carrier preparation of prostaglandin E1 has special affinity for diseased blood vessels and aggregates at high concentrations in diseased tissues, which can improve the efficacy of prostaglandin E1, exert its targeting effects, act directly on spastic glomerular arteries, smooth muscle cells and thylakoid cells, increase renal blood flow, reduce renal vascular resistance, regulate small glomerular inlet and outlet arteries, reduce glomerular capillary pressure, prevent ischemia, improve blood flow, and control proteinuria.
2.2. Diabetic retinopathy. In economically developed countries, diabetic retinopathy is a major blinding eye disease, and its development, closely related to the age of onset of diabetes, duration of disease, genetic factors and diabetes control, hypertension, hyperlipidemia and high blood viscosity status are also relevant factors for its development. Prostil has been shown to have significant efficacy in hypertension, hyperlipidemia, and hypervascularity, and has a significant protective effect on vascular endothelial function. Wu Fanglai et al [14] randomly divided 109 patients with diabetic retinopathy into 52 cases in the treatment group and 57 cases in the control group. The treatment group was treated with prostilbestrol 10ug intravenous push once a day for 14 days, and the changes of visual acuity, visual field and fundus angiography of the patients were observed before and after the treatment. The results showed that the visual acuity of the treated group increased significantly, the gray value of the visual field decreased, and the number of microaneurysms and hemorrhagic spots in the fundus decreased, leading to the conclusion that prostilbestrol injection has a significant therapeutic effect on early diabetic retinopathy.
3. Diabetic neuropathy. Diabetic neuropathy is one of the most common and complex complications of diabetes mellitus. Both central and peripheral nerves can be involved. Microangiopathy is the most important factor causing diabetic motor neuropathy. Pathological examination shows mainly ischemic damage of blood vessels, such as axonal degeneration, nerve fiber reduction, focal nerve sheath necrosis and thickening with neuromas and neovascularization or nerve fiber swelling. The narrowing of the walls of the perineural trophoblastic vessels, thickening and hyaline degeneration of the basement membrane, deposition of PAS-positive material in the vessel walls, swelling of endothelial cells, and hyperplasia of the intima and smooth muscle lead to impaired circulation, which, together with the hyperviscosity state of diabetic blood and high platelet aggregation, cause hypoxia in the nerve endothelium and lead to axonal myelin degeneration. This gives the basis for the treatment of diabetic peripheral neuropathy with prostilbestrol, which as a vasoactive drug has a strong vasodilatory effect, inhibits platelet aggregation, improves microcirculatory perfusion, and has an oxygenating function that enhances ATP production. Therefore, prostilol can effectively improve neuroischemia and hypoxia in diabetic patients. By Meta-analysis of controlled studies of prostilbestrol in the treatment of diabetic neuropathy reported from January 1994 to December 2006 across China, Nie Lihong et al [15] found that: prostilbestrol significantly reduced clinical symptoms and improved nerve conduction velocity in patients with diabetic peripheral neuropathy, and its efficacy was significantly better than that of currently used drugs (P<0.001), and no significant side effects were observed The efficacy of prostilbestrol was significantly better than that of the currently used drugs (P<0.001), and no significant side effects were observed. Liu Lihui et al [16] randomly divided 60 patients with diabetic peripheral neuropathy into prostaglandin treatment group and control group, both groups were given strict glycemic control treatment, the treatment group was treated with prostaglandin 10ug in 0.9% sodium chloride injection 100ml intravenously, once a day; the control group was treated with vitamin B1 100mg, methylcobalamin 50ug intramuscularly, once a day. The duration was 4 weeks for both groups. It was found that the total effective rate of improvement of symptoms and signs of patients in the treatment group reached 80%, which was significantly better than that of the control group; the MNCV and SNCV of median nerve and common peroneal nerve of patients in the treatment group were significantly different before and after treatment (P<0.05), and there was also a significant difference between the treatment group and the control group after treatment (P<0.05), and the patients tolerated prostilbestrol well. The patients in the two groups with significant effects were also found to have better long-term results than those in the control group after 1 year of telephone follow-up.
4. Diabetic foot. The occurrence of diabetic foot is associated with lesions of large, small and microvessels, as well as neuropathy. Vascular lesions lead to malnutrition in the distal lower limbs of patients, peripheral neuropathy makes patients lose pain sensation, and some trauma cannot be detected in time, which easily causes mechanical injury combined with infection, and the main role is played by arterial occlusion and tissue ischemia. Prostaglandin E1 inhibits platelet aggregation and reduces platelet adhesion rate; inhibits vascular smooth muscle cell proliferation, lowers blood lipids, and inhibits the formation of atherosclerosis; causes vascular smooth muscle diastole to achieve the effect of diastolic lower limb arterial vascular. Wang Weidong et al [17] gave interventional treatment followed by prostilbestrol 40ug intravenous drip once a day for 21 days in 85 patients with diabetic foot, resulting in an efficiency rate of 88.9% in patients. Tao Lu et al [18] in 43 patients with diabetic foot under comprehensive treatment of diet control, application of insulin, effective antibiotics and debridement and local treatment, the treatment group was also given prostilbestrol 10ug intravenous push once a day for 3 months with discontinuation of other anticoagulant, vasodilator and nerve nutrition drugs, and the total effective rate was 90.9%. The posterior tibial nerve conduction velocity and dorsalis pedis artery blood flow velocity were improved after treatment. It indicates that prostil not only can improve the peripheral circulation of diabetic foot patients, but also has a positive effect on the recovery of damaged nerve function and can promote the healing of recalcitrant diabetic foot ulcers.
In summary, prostilbestrol not only has the effect of dilating blood vessels and reducing cardiac load, but also has the effect of regulating water-sodium balance, diuretic, cardiotonic, improving coronary circulation, protecting myocardium, improving microcirculation, stabilizing lysosomal membrane, scavenging non-protein nitrogen, protecting renal function, scavenging immune complexes, inhibiting platelet aggregation, and improving hypercoagulability [19]. Mansinto is a lipid microsphere carrier preparation of prostaglandin, which lipidizes the prostaglandin molecule, reduces its fire extinguishing in the lungs, plays an important role in microcirculation regulation under normal conditions, and has a special affinity for lesion vessels under pathological conditions, aggregates at high concentration in lesion tissues, and can better aggregate at inflammatory lesions and blood vessels to improve the efficacy of prostaglandin and exert its targeting effects. Therefore, Mansinto (Prostil) is widely used in the treatment of chronic complications of type 2 diabetes mellitus and has a broad therapeutic prospect.
Reference.
1. Liu Qiu-Li,Li Y-M,Zhang X-F. Clinical observation on the treatment of diabetes mellitus combined with coronary artery disease with prolidil. Chinese Medical Innovation. 2009 Nov,Vol.6 No.31:183.
2. Zhang Yan,Huang Xiaoyan,Li Caiping et al. Effect of prostaglandin E1 on blood rheology in patients with type 2 diabetes mellitus combined with coronary artery disease. Journal of Practical Medicine. 2006 Vol. 22 No. 23:2774-2776.
3. Yang Y,Zhu L. Study on the effects of pregabalin on lipids and blood rheology in patients with type II diabetes mellitus combined with coronary heart disease. West Med. 2012 Mar. vol. 24, no. 3:531-532.
4. Li Xianhou, Hou Ying, Wang Yiwei, Feng Kun. The efficacy of prostaglandin microsphere carrier preparation in the treatment of diabetic cerebral infarction in 32 cases. Heilongjiang Med. 2001, Vol. 25, No. 10: 759-760.
5. Li H,Dai Q. Effect of Prostigil on Blood Rheology in Patients with Type 2 Diabetes Mellitus Combined with Cavernous Cerebral Infarction. Journal of Practical Clinical Medicine. 2010 Vol. 3:35-36.
6. Wang A. H., Ji Q. H., Xu X. J., Zhang S. L. et al. Clinical study on the treatment of lower limb arterial occlusive disease complicated by type 2 diabetes mellitus with prolidil injection. Chinese Journal of Endocrinology and Metabolism. 2009 Dec. vol. 25, no. 6:608-609.
7. Huang Xiaozhong,Zhang Jiwei,Guo Daqiao et al. Clinical study on the treatment of lower limb atherosclerotic occlusive disease with prolidil injection. Shanghai Med. 2011 Vol. 32 No. 12:598-600.
8. Liu JF. The efficacy of prolidil in the treatment of early diabetic nephropathy. Jilin Med. 2010 Jun. vol. 31, no. 18:2835-2836.
9. Cao Xueying, Tang L, Wei R. Cell. Clinical observation of proteinuria in diabetic nephropathy treated with prolidil. Chinese Journal of Practical Medicine. 2007 Mar. vol. 2, no. 7:36-38.
10. Zhang, Yu D-M, Zhao W, Li S-Y. Effect of prolidil on urinary protein in patients with diabetic nephropathy. Chinese Journal of Diabetes.2002 Vol.05:276-279.
11. Zhang JH,Feng WQ. Clinical analysis of 42 cases of diabetic nephropathy treated with prostaglandin E1. Journal of Xuzhou Medical College. 2002 Vol. 22 No. 6:550-551.
12. Zhang Huijuan,Kuang Hongyu,Jiang Xiaoyan,Sun Hong. Efficacy of adjuvant treatment of diabetic nephropathy with prostaglandin E1. Journal of China-Japan Friendship Hospital. 2007, Vol. 21, No. 1: 39, 43.
13. Mou Yaru, Study on cytokines and apoptotic mechanism of prostaglandin E1 in the treatment of diabetic nephropathy. Shandong University. 2010: Master’s thesis.
14. Wu F L, Wang S H, Huang D X, Bo W. Clinical observation on the treatment of early diabetic retinopathy with prolidil. Chinese Contemporary Medicine. 2011, Vol. 18, No. 33:70-71.
15. Nie LH,Jiang YB,Li GC. Systematic evaluation of prolidil in the treatment of diabetic peripheral neuropathy. Guangdong Med. 2007 Jun. vol. 28, no. 6:988-989.
16. Liu LH,Shi NaiXin,Xu Y. 60 cases of diabetic peripheral neuropathy treated with prolidil. Chinese Journal of Gerontology. 2011 Aug. vol. 31, no. 16:3185-3186.
17. Wang W.D., Liu L.Q., Xing L. Clinical efficacy of prolidil combined with interventional therapy on diabetic foot. China General Medicine. 2010 Aug No. 23:2548-2550.
18. Tao L,Zhou SJ,Ma XW,Sun L. Effect of prostaglandin E1 in the treatment of diabetic foot ulcers. Qilu Medical Journal. 2005 Apr Vol. 20 No. 02:130-131.
19. Li Y,Tang J. Advances in the pharmacological study of prolidil. Southwestern Military Medicine. 2006 Dec. vol. 8, no. 6: 79-81.