2 English reference protease inhibitors
Overview Protease is a specific aspartyl protease in the gene encoding human immunodeficiency virus. Its function is to split protein produced by genes and gene expression into active viral structural proteins and enzymes, which is the key substance to inhibit HIV replication.
Protease inhibitor is a chemical analogue for the treatment of AIDS. Protease is a specific aspartyl protease encoded by human immunodeficiency virus gene. Its function is to decompose protein produced by genes and gene expression into active viral structural proteins and enzymes, which play a key role in the replication of HIV virus.
Protease inhibitor is a kind of polypeptide compound, which is an important part of anti-HIV drug combination therapy. It is a new product in the middle and late 1990s. The difficulty in drug synthesis is also the main reason for the high cost of anti-AIDS treatment at present. It's called "must cross obstacles" Protease inhibitors mainly include: nelfinavir, saquinavir, indinavir, ampanavir, ritonavir, lopinavir and compound preparations.
Indications for the treatment of HIV 1 infection.
5 is characterized by peptide-based compounds, which either competitively inhibit protease activity or act as inhibitors of complementary protease active sites. These drugs can inhibit the activity of protease, which mainly acts on the last stage of HIV replication. Because protease is inhibited, DNA formed from infected CD4 cells cannot be aggregated and released.
6 Mechanism of Action Precursor proteins encoded by retrovirus genes such as HIV need to be decomposed into functional structural proteins under the action of protease before they can be assembled into complete virus particles. Protease inhibitors can combine with viral protease catalytic genes to inhibit enzyme activity, resulting in the failure of protein precursors to crack into mature virions.
7 Adverse Reactions Dr Joan Stephenson published an article in the Journal of Medical News and Perspectives of the American Medical Association, saying that researchers in the United States, Canada and Australia found that some patients receiving anti-HIV treatment had abnormal fat distribution after taking protease inhibitors.
The researchers found that after taking protease inhibitors for 3 months or more, some patients showed abnormal deposition of adipose tissue under the condition of constant weight, which was characterized by "buffalo back" (that is, fatty tissue at the bottom of the neck), pot-shaped abdomen or "full moon face". However, some patients have fat consumption in limbs or face after taking protease inhibitors. The above symptoms are very common in patients with Cushing syndrome. The syndrome is caused by abnormal elevation of serum corticosterone, but no evidence of elevated serum corticosterone was found in these patients. At least four protease inhibitors can cause abnormal fat deposition: indinavir, nelfinavir, ritonavir and saquinavir. Researchers at the National Institutes of Health (NIH) found that after taking indinavir, the fat was not deposited under the skin, but around the abdominal organs through CT scanning of 10 patients with increased abdominal circumference. It is not clear how protease inhibitors cause the above symptoms. Some studies have shown that protease inhibitors may affect metabolic function, causing the increase of triglycerides and blood sugar, insulin resistance and diabetes, but these abnormalities have not been found in these patients with fat deposition. Similarly, it is not clear whether fat deposition is reversible after dressing change.
Therefore, the researchers believe that long-term clinical trials and after-sales supervision should be carried out for these drugs to understand the incidence of this complication and possible treatment methods.
8 Drug Interaction This product can be used in combination with ritonavir to improve the curative effect, and is used to treat HIV that is ineffective in other antiretroviral therapies.
9 Toxic side effects The US Centers for Disease Control and Prevention (CDC) Hoimberg reported that the use of protease inhibitors can increase the risk of myocardial infarction in HIV- 1 infected people, although the incidence rate is not high. Protease inhibitors are effective in treating HIV- 1 infection, but they can increase the risk of hyperlipidemia and hyperglycemia and lead to insulin resistance. Therefore, some people worry that long-term use of protease inhibitors will increase the risk of myocardial infarction, angina pectoris and cerebrovascular accident. During 2002 1993 1 to 1, Hoimberg et al. conducted a long-term observation on 5,672 HIV- 1 infected patients in 9 HIV clinics in 8 cities in the United States (177 12.4 person-years). The average age of the patients was 42.6 years old, and 82% of them were male. ? The Lancet 2002? 360? The results of 1747 showed that 1996 used protease inhibitors, and the incidence of myocardial infarction increased several years later (trend test, P = 0.0 125). Of the 3247 patients who used protease inhibitors, 19 had myocardial infarction (1.421000 person-years), while of the 2425 patients who did not use protease inhibitors, only 2 had myocardial infarction (0.046/ 1000 person-years). The ratio is 7. 1, and 95% CI is 1.6 ~ 44.3. The adjusted risk ratio of Cox proportional hazard model is 6.5, and the 95% CI is 0.9 ~ 47.8. The use of protease inhibitors has no significant effect on the incidence of myocardial infarction. * * * Angina pectoris 15 cases, of which1/kloc-0 cases were treated with protease inhibitors (ratio: 1.93, 95% CI: 1.63 ~ 5.95). There were 65438 04 cases of cerebrovascular accident, 7 cases in each group. Researchers believe that protease inhibitors increase the risk of myocardial infarction, but the incidence of myocardial infarction is not high, which usually occurs in patients with other cardiovascular risk factors. Patients infected with HIV- 1 should not stop using protease inhibitors. Early smoking cessation, diagnosis and treatment of hyperlipidemia, improvement of insulin resistance and antihypertensive treatment can reduce this complication of protease inhibitors.
10 future development According to the statistical data released by the Ministry of Health in early 2006, by the end of 2005, there were about 650,000 people infected with AIDS in China, and about 60,000 to 80,000 people were newly found with AIDS last year, with an average of about 200 people newly found every day. The rapidly expanding number of patients means a rapidly expanding drug market.
Facing the huge market space, domestic anti-AIDS drug manufacturers are not enthusiastic enough. * * * The drug bidding system has reduced the profits of enterprises to the lowest point. As a result, the independent research and development ability of enterprises is reduced.
As an important AIDS drug, the protease inhibitor market is an attractive big cake. However, although foreign multinational companies constantly introduce newer protease inhibitors and have been leading the anti-AIDS drug market, there are few applicants and few varieties in the domestic market. At present, there are only three kinds of protease inhibitors approved by the US Food and Drug Administration (see attached table for details). Take the statistics of the 16th National Congress as an example. From 2002 to 2005, only indinavir, a protease inhibitor, entered the statistics, and all of it was provided by Merck. This is mainly because the synthesis process of protease inhibitors is difficult. At present, the protease inhibitors listed abroad, such as saquinavir, indinavir and ritonavir, all have intellectual property problems in terms of compounds and preparation processes to varying degrees in China, and domestic manufacturers can not copy them for the time being.
Although the domestic anti-AIDS drug market is gradually maturing, in the field of protease inhibitors, China is still in its infancy. Although in the future, with the expiration of patents of other protease inhibitors, domestic enterprises will compete for imitation and the variety will increase, but the competition will be more intense. By then, pharmaceutical companies will not only compete with imported drugs for the market, but also face competition from domestic enterprises. Therefore, driven by the growth of the whole AIDS drug market, the market of protease inhibitors is also expanding correspondingly. Domestic anti-AIDS drug manufacturers should not be blindly optimistic about the market position they have achieved at present, but should pay close attention to the dynamics of the international market and actively respond to the challenges and impacts of the latest research and development trends and products.
1 1 Newly edited pharmacology from related sources
12 related drugs