Future Cardiovascular Drug R&D Tendency to Develop Compound Herbal Medicine

Business News Agency, September 6th With the increase of cardiovascular diseases, reducing the incidence of cardiovascular diseases and mortality has become an increasingly pressing major public health issue.

Cardiovascular disease has become one of the highest mortality rates in the world. According to incomplete statistics, currently an average of 17.5 million people die from cardiovascular disease and stroke each year, accounting for 1/3 of all deaths. It is estimated that by 2020, the number of deaths due to cardiovascular diseases will reach 25 million people worldwide. Therefore, for tens of millions of patients with global cardiovascular disease, especially those at high risk for cardiovascular disease, how to reduce cardiovascular disease morbidity and mortality through effective interventions has become an increasingly urgent and important public Hygiene issue.

A century ago, cardiovascular disease was only a secondary cause of death and disability, but it is now one of the leading causes of death worldwide. The number of hypertensive patients worldwide may increase by 60% in the next 20 years. Among them, the growth of developing countries and regions will be even more significant, reaching 80%, and that of developed countries will increase by about 24%. The rapid increase in the number of cardiovascular disease patients brings a huge market for cardiovascular drugs, and the future of cardiovascular drugs in the world has broad prospects. In 2008, the total size of the global cardiovascular drug market has exceeded 100 billion U.S. dollars, equivalent to 16% to 17% of the total sales of the international pharmaceutical market, of which, drugs that affect the renin-angiotensin system have increased by 30.3%. Protective agent 58.4%.

Compound drug development blooms

In the control of multiple risk factors, the joint control of antihypertensive therapy and blood lipid compliance is the direction of cardiovascular drug research, mainly reflected in the control of the same risk factor, the combination of different mechanisms of drug use and the introduction of compound preparations, in order to obtain Better control effect. Compounds with different lipid-lowering mechanisms, such as ezetimibe/simvastatin, nicotinic acid/lovastatin, etc. Compounds composed of different hypoglycemic agents, such as rosiglitazone/metformin; different antiplatelet mechanisms Composition of the compound, such as aspirin/cliprexrel; joint control of different risk factors, such as compound preparations for antihypertensive and lipid lowering therapy; combination of antiplatelet agents and lipid-lowering therapy; reduction of homocysteine ​​and hypotension Drugs and so on.

As for the development of compound drugs, research is currently being conducted on the interactions between drug chemistry, pharmacokinetic interactions, drug efficacy, and safety. Those pharmacological effects are synergistic and additive, and adverse reactions are Antagonists, combination drugs and clinical trials based on adequate population safety composition of the drug composition.

Strengthen Research Methods of New Drugs

As cardiovascular treatment drugs are already quite abundant, in many therapeutic areas, under the control of multiple risk factors, it is further shown that new drugs have considerable difficulty for cardiovascular special effects, and at the same time, the continuous exposure of drug safety events makes the public And the safety requirements of drug administrations are also increasing. In this regard, the “critical path” action adopted by the FDA in the US is still worth learning from, such as research on pharmacokinetic/pharmacological model studies and early exploratory clinical studies on small doses, and has the potential to optimize early clinical studies. More targeted, and adaptive clinical design may have more realistic implications for improving the success rate of larger clinical trials.

Important point

New targets for new mechanisms emerge in an endless stream

With the development of basic medicine, molecular biology and functional genomics, and proteomics, people have continued to deepen research into the occurrence and development process and pathophysiological mechanisms of physiology and disease, and vigorously carried out research on disease epidemiology, constantly discovering new possibilities. The pathogenic factors, these have promoted the emergence of new drug targets. The combination of high-throughput screening and computer simulation technology has enabled new drug candidate molecules to emerge with the emergence of new targets, which are particularly prominent in the cardiovascular field.

Renin-Angiotensin-Aldosterone: Protecting Kidney

The renin-angiotensin-aldosterone system (RAAS) remains an important target for the development of hypertension drugs. Among them, representative new target drugs are aliskiren and eplemerenone. Aliskiren has a sympathetic effect by blocking the RAAS system and may prevent reflex tachycardia after dilation of blood vessels, improving the hemodynamics of patients with heart failure to a certain extent, and has a protective effect on the kidneys. As a result, it has attracted the attention of the medical community.

In clinical trials, aliskiren first showed a clear antihypertensive effect compared with placebo and currently available drugs, and then showed its effectiveness in ongoing target organ protection clinical trials for patients with diabetic nephropathy and heart failure. Significant. Eplerenone is a highly selective congenial corticosteroid receptor blocker. In 2002, it was approved for the treatment of hypertension in the United States. Its main clinical trials are also focused on heart failure patients. It can be seen that, for drugs that antagonize the RAAS system, exploring the protection of target organs such as the kidneys and heart and improving the long-term prognosis of patients with heart failure has become the main target for the development of new drugs.

In addition, ATP-sensitive potassium channels are currently being studied as targets for antihypertensive drugs, and their specific opener may play a role by inducing vascular smooth muscle potassium currents and reducing the pathological elevation of endothelin levels in hypertensive states. Its antihypertensive effect and safety still need a series of clinical trials to confirm. For the risk of developing such new drugs, there is both the risk from the drug target and the risk of the compound itself.

Based on the above new research on hypertension drugs, it is not difficult to see that for the new target and mechanism of action of the drug, it has been proved that it has a clear antihypertensive effect, which is the basis for further research of all new drugs. This is reflected by the absolute antihypertensive effect compared with placebo and the relative degree of hypotensive compared with active drug. However, because of the large fluctuation of blood pressure, the quality control of clinical trials is particularly important. At the same time, the stability of antihypertensive effect needs to be examined. Therefore, the protection of target organs of antihypertensive drugs has become a hot spot in clinical research. Although the current research on the protective effect of target organs has not become a necessary condition for the listing of antihypertensive drugs, more and more new products are being developed for such research. In particular, the measurement and evaluation of the beneficial protective effects of organs such as heart, brain, and kidney are also being continuously explored and confirmed. Other effects on mortality and cardiovascular events need to be further studied after the launch of new drugs.

Lipid-regulating drugs: Elevated HDL drugs developed into hot spots

Looking at the current concept of commonly used lipid-regulating drugs in clinical practice, it mainly includes: lowering cholesterol will bring benefits to patients, with the increase in the degree of cholesterol reduction, the benefit of patients will increase; for different risk stratified patients, design different blood lipids standards Level, for patients with coronary heart disease, diabetes, high blood pressure, smoking and other risk factors, should set a lower cholesterol level in order to exert its further protection; for cholesterol there is a lower limit, the lower the cholesterol, the better There are still different views; however, it is the consensus of the medical and health community that actively conducting lipid-adjusting interventions.

Although the lipid-lowering effects of currently listed statins have been widely recognized, there is still a low overall compliance rate. For this reason, the newly-marketed potent statins, such as rosuvastatin and pitavastatin, have reduced the effect of low-density lipoprotein in clinical trials by more than 40%, and the rate of compliance has also been significantly increased. Meet targets without excessive dose adjustments. The current research on statins is mainly focused on: superior lipid-lowering effect, better long-term use safety, lipid-lowering effects, and clinical endpoint improvement.

In the field of lipid-regulating drugs, the current development and research of drugs that raise high-density lipoprotein (HDL) are gaining favor in the industry. Can elevated HDL improve the clinical outcome of patients with cardiovascular disease? Will HDL compliance become another new lipid-regulating goal after LDL? All of this requires the design and testing of clinical trials to prove. It has been reported that clinically targeted trials of this type have been designed. Specifically, based on the powerful LDL indicators, high-dose sustained-release niacin is used to increase HDL, and it can be observed whether it can reduce long-term clinical cardiovascular disease in patients. The occurrence of events and deaths. Niacin is a traditional HDL-elevating drug. CETP, as a new drug target, promotes the translocation and exchange of cholesteryl esters (CE) and triglycerides (TG) in plasma lipoproteins. The inhibition of CETP may be a new one. Improve the level of HDL-C, thereby reducing the incidence of cardiovascular events. Although the first novel HDL-risk CETP inhibitor drug molecule, Torcetrapib, was forced to stop being tested due to high blood pressure and increased patient mortality, a molecular study of a subsequently developed CETP inhibitor showed no increase in blood pressure, Similar tests are in progress.

Antiplatelet drugs: Blood coagulation factor Xa inhibitors are concerned

At present, the research of antiplatelet drugs mainly focuses on two aspects. One is the strength of antiplatelet, ie considering the adequacy of antiplatelet therapy. Some studies believe that there is still room for further improvement of the current antiplatelet therapy; the second is antiplatelet. Speed, with the development of emergency coronary interventions, how to conduct adequate interventional procedures, how to perform adequate interventional anti-platelet therapy before and during injury, and once surgery and coronary artery bypass graft surgery, How to control bleeding during surgery due to anti-platelet effects has become a thorny issue for new drug research.

At present, antiplatelet drugs are required to have the following characteristics: First, short half-life and ultrashort-acting effects, once stopped, platelet function can be restored in a short time; secondly, intravenous administration can be achieved; third, reversibility of antiplatelet effect can be achieved. . Due to these features, rapid antiplateletization can be performed during the interventional procedure, reducing the preparation time for interventional therapy and the occurrence of thrombotic events during the surgical procedure, while also facilitating the withdrawal of the intravenous route, the short half-life, and the effect on platelets. The reversibility of the patient makes it necessary to perform emergency surgery without increasing the risk of extra bleeding and less bleeding. Due to the combined use of a variety of anti-hemoglobin drugs, the safety of bleeding has become a major focus of drug development and clinical trials.

Currently, in the development of new anticoagulant drugs, inhibitors of coagulation factor Xa are of the greatest concern. Among them, oral anti-Xa drug research has made progress. The development paths followed by these new drugs are: first, prevention and treatment of deep venous thrombosis in patients with lower extremity bone and joint surgery, followed by prevention and treatment of clinical end points in patients with atrial fibrillation and acute coronary syndrome, and finally Hypercoagulable state with antithrombotic therapy in people with high thrombosis to reduce embolism in pulmonary embolism and systemic circulation.

Pulmonary hypertension: focus on clinical endpoints

In the research and development of pulmonary hypertension drugs, research on endothelin receptor antagonists has focused on walking distance and improvement of major hemodynamic parameters (pulmonary arterial pressure, pulmonary vascular resistance, mean pulmonary artery pressure, pulmonary capillary wedge pressure) The beneficial effects, as well as clinical endpoints (such as prolonging the time of first onset and reducing the incidence of malignant events in patients with symptomatic pulmonary hypertension) were the primary endpoints of clinical studies. Among them, nitric oxide-guanylate cyclase-cyclic guanosine monophosphate is becoming an important target for the development of pulmonary hypertension. In addition, the use of different doses of sildenafil in combination with endothelin receptor antagonists is also under investigation.

Anti-AF: New Drug Enters Clinical Stage

Drugs for the treatment of atrial fibrillation have always been a research hotspot in the medical field. The main reason for this is that atrial fibrillation is the most frequent persistent arrhythmia. The onset of atrial fibrillation has become increasingly important with the advent of social aging, and its central causes of stroke and acute coronary syndromes are the major potential health risks associated with atrial fibrillation.

Studies have shown that non-valvular atrial fibrillation can increase the risk of stroke by 17 times. At present, the drug development in AF is mainly considered in two aspects: on the one hand, the use of multiple anticoagulants in atrial fibrillation disease in order to reduce the incidence of embolism; on the other hand, it is not totally dependent on sinus rhythm or improvement of heart rate control. Atrial fibrillation or atrial flutter. The most representative of these is Multaq, which has entered the late phase of clinical trials and achieved good results.