Proton pump refers toBiomembraneBoth sides of the upside down membraneHydrogen ionElectrochemical potential differenceprotein（protein）。When the proton pump pumps out hydrogen ions, the pH gradient andPotential gradient。Proton pump maintainedPotential difference（difference potential）ForcationAcrossProtoplasm membraneThe transportation ofdriveThe carrier on the protoplasm membrane controls the rate and selectivity of cation transport.Protons caused by proton pumpconcentration gradientAlso proton andanionThe collaborative transmembrane transport of provides the driving force.adoptCytochemical technologyandElectron microscopyIt has been found on plant protoplasm membraneATPaseUnevenDistributed inCell membraneEndoplasmic reticulum（Endoplasmic reticulum, ER）Andmitochondrial membraneOn the system.[1]
Exists inBiomembraneIs an electrochemical potential difference (△ μ H+）And actively transport H+OfMembrane protein。In a narrow sense, it refers to the decomposition of ATP and transportation of H+, or use the energy from H to synthesize the H of ATP+- ATPase，H+-ATPase exists in mitochondria andchloroplastThe main means of obtaining energy for living beings.Broadly speaking, it also includes the direct conversion of light energy into transport of proton energyBacteriorhodopsin (bR), and transport of protons through the energy transferred by electronsCytochrome C oxidaseAnd NADH – NADP transhydrogenase, etc.
reversibilityATPase, canExternal energyDriven reverse concentration transfer H+。Mitochondrial intimarespiratory chainThere are three enzyme complexes with proton pump function in H+They are: cytochrome c oxidaseCoenzyme QHtwo– Cytochrome creductase、NADH– Coenzyme Q reductase.Proton pumps are commonly found on the plasma membrane of bacteria, and some are accompanied by respiratory chain components.Halophilic bacteriaBacteriorhodopsin on membrane（bacteriorhodopsin）Driven by light, H+It is transported into the bacteria body for concentration.
Action mechanism
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electron transportResulting in conformational changes in the complex.The proton transfer isamino acidSide chainPK valueThe effect of change.The conformational change changes the pK value of the amino acid side chain, resulting in the side chain that plays the role of proton pump being exposed and alternately exposed toMitochondrial intimaThe inside or outside of the, which makes the proton shift.This system is considered as the mechanism of proton pump.[2]
classification
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There are four types of proton pumps: P-type and V-type[3], F-type, and ABC superfamily.
Features: Transfer H+The process involves phosphorylation and dephosphorylation
Carrier proteinutilizeATPIt phosphorylates itself and changes the conformation to transfer protons or other ions, such asplant cellH on membrane+Pump,Animal cellNa of+–K+Pump, Ca2+Ion pump, H+–K+ATPase(located in stomachEpidermal cell, secretes gastric acid).
ThisSuperfamilyContains hundreds of differentTransporter, is the largest class of transport proteins.Eachabc transporterIt is specific for the substrate or its group.[5]
inhibitor
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Proton pump inhibitor
HumanGastric wallThere are h2 receptors to stimulate h+secretion and proton pumps to transport h+, which perform their own duties and secrete sufficientgastric acidTo promote digestion of food.However, the secretion of gastric acid is also affected by nerve, endocrine and other factors, so the secretion of gastric acidRegular meetingsAbnormal. When there is no food in the stomach, excessive gastric acid secretion keeps the stomach atAcidic environmentIn the long run, it is easy to causegastric mucosaulcer, erosion, evenGastric bleeding。gastric acidReflowThe esophagus adjacent to the stomach is also doomed, causingHeartburnFelt as the main symptomGastroesophageal refluxDisease (gerd).Peptic ulcerAnd gastroesophageal reflux disease are gastric acid related diseases.There are many drugs to treat gastric acid related diseases.The earlier used acid inhibitor is h2 receptorAntagonist(h2ras), such asCimetidine、Ranitidine、FamotidineEtc.These drugs, which were popularized in the 1980s, were believed to provide safe and effective acid suppression at that time. However, it was soon found that due to many factors affecting the h2 receptor, the individual differences of patients were large, and acid secretion was easy to occur when h2 receptor antagonists were used to treat peptic ulcerRebound phenomenonandTolerancePoor and other problems.By the 1990s, scientists had focused their research onProton pump inhibitor(ppi).The advantage of ppi is that it can more directly inhibit the final step of gastric acid secretion, and its efficacy is significantly better than other acid inhibitors, while solving many problems such as tolerance.
The ppi drugs on the market areomeprazole、Lansoprazole、Pantoprazole、RabeprazoleAmong them, omeprazole is the most widely used.Chemistry of these ppi productsStructural similarity，Action modeSimilar, but due tohalf lifeDifferent,Clinical efficacyThey are also different.Ppi plays an important role in the activation of proton pump to achieve the purpose of acid suppression, which can comprehensively alleviate the symptoms of peptic ulcer and gastroesophageal reflux disease.However, after extensive clinical use, some shortcomings of ppi have also been exposed, such as the maximum acid suppression effect can be achieved after 3 days of use, poor control of intragastric PH at night, and the symptoms of gastroesophageal reflux disease mostly occur at night.Due to these limitations, in the next 10 years, scientists will focus on how to optimize ppi to achieve better acid suppression effect, so as to improve theQuality of life。So far, at least three methods to improve ppi have been found:RacemizationCorporealEnantiomerTo improve the biochemical characteristics of ppiPrecursorsChange the half-life of ppi and develop an antagonist of proton pump.
Ppi including omeprazoleStructuralBoth are included inEnantiomerThis is like two hands of a person. Although they look very similar, their structures are not the same, so the functional differences are also significant.If simple isomers can be developed, it is of great significance for the acid inhibition effect.It is reported that the first single isomer ppi (i-ppi) is the s-enantiomer of omeprazoleEsomeprazoleHas been the first to come out.In a double blindCross testIt was found that the efficacy of esomeprazole 40mg was more significant than that of omeprazole 20mg.The so-called method of using prodrugs to change the biochemical characteristics of ppi is simply to add a chemical group on ppi to form ppi precursors. Compared with all proton pump inhibitors, this new compound will be more stable, can effectively extend the release of ppi, and enable more drugs to inhibit the activated proton pump for a longer time.The development of proton pump antagonists is another hot spot in the study of regulating intragastric PH.Compared with ppi administered once a day, proton pump antagonists administered twice a day (such asimidazolepyridine）It works faster, and can better control the intragastric PH value during the day and at night.
Gastric acid secretion
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The maximum concentration of H+in gastric juice can reach 150mmol/L, which is three or four million times higher than that in blood. Therefore,Parietal cellSecretion of H+is carried out against a huge concentration gradient, which requires a large amount of energy, which comes from oxygen metabolism.The H+needed for acid secretion comes from the water in the cytoplasm of the parietal cells.Hydrolysis dissociation produces H+andOH⁻By the action of H+, K+- ATPase on the secretory tubule membrane of parietal cells, H+is actively transported into the lumen.wallCell secretionThe H+, K+– ATPase on the tubular membrane is also called proton pump or acid pump.H+– K+exchange is a prominent feature that distinguishes the parietal cell proton pump from the proton pump on any other cell in the body.H+, K+– ATPase catalyzes the decomposition of a molecule's ATP into ADP andphosphoric acidThe energy released can drive one H++to enter the secretory lumen from the wall cytoplasm and one K++to enter the cytoplasm from the lumen.The secretion of H+can only be carried out when there is sufficient concentration of K+in the secretory tubules.Drugs that selectively interfere with H+, K+- ATPase of gastric parietal cells have been used to effectively inhibit gastric acid secretion, becoming a new generation of anti ulcer drugs.The known parietal cells contain abundantCarbonic Anhydrase (CA), under its catalysisCellular metabolismCO ₂ produced and absorbed from plasma can rapidlyhydrationThe formation of H2CO ∨ then separates into H+and HCO ∨.In this way, after the secretion of H Γ, the OH ⁻⁻ remaining in the cell will be neutralized by combining with H Γ separated by H ₂ CO ∨, and the pH in the parietal cell will not rise due to the accumulation of OH ⁻.HCO ≮ produced by H ₂ CO ∨ enters the blood at the bottom membrane of parietal cells in parallel with CI ⁻.Therefore, after meal, when a large amount of gastric acid is secreted, the PH of blood and urine tends to rise and appear“Postprandial alkali”。CI ⁻, which exchanges with HCO ⁻ and enters the parietal cells, enters the lumen through the specific CI ⁻ channel on the secretory tubule membrane, and forms HCI with H ⁻.
Researchers are very concerned about the potential side effects of proton pump inhibitors, especially in long-term use.Especially, the powerful effect of proton pump inhibitor can cover upgastric cancerAnd delayed diagnosis, although prolonged exposure may accelerateGastric carcinoidGrowth of.
objective
ResearchAustraliaTasmaniaThe use of proton pump inhibitors for patients in major teaching hospitals mainly determines whether the treatment is appropriate according to the published guidelines.
method
Retrospective evaluation of all inpatients taking any proton pump inhibitor for more than 7 monthsmedical record。At the same time, ask these inpatients a series of questions to obtain some relevant information, especially if or when these patients have undergone Endoscope examination.
result
200 patients (52% male),average age69 ± 16.4 years old.The most common indication for using proton pump inhibitors is acute gastrointestinal bleeding (20.9%), which is severeIntractabilityUlcerativeEsophagitis(17.3%), mild/moderate esophageal reflux (17.3%) and refractory peptic ulcer (11.7%).
Many patients use proton pump inhibitors (39.6%) due to "other" indications.Only 37.1% of the cases were prescribed proton pump inhibitors in accordance with the approved indications described by the Australian Pharmaceutical Interest Plan.54.1% of patients underwent endoscopy before starting proton pump inhibitor treatment, and 12.8% of patients underwent endoscopy within the next 7 days.Only 59% of patients had received PPI before starting PPI treatmentH2 receptorAntagonist treatment.To make matters worse, only 58.5% of patients used H2 receptor antagonists to treat mild/moderate esophagitis before proton pump inhibitor treatment.Treatment course of proton pump inhibitor for patients admitted to the hospital and who have received a drugmedian450 days.More than half of the patients were treated with other drugs at the same time, which can cause or aggravate stomach esophagus diseases, and 18% of the patients smoked.
conclusion
Although proton pump inhibitors are undoubtedly effective drugs, studies on their prescription practice have always suggested that they should be overused before endoscopy, used for patients who do not meet the approved standards, and used for indications that "low-intensity" drugs are very effective for patients' symptoms.This has aroused economic and safety concerns, especially according to the suggestion that these drugs can delay the diagnosis of gastric cancer.
global market
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At the end of the 20th century, proton pump inhibitors blossomed and fruited.LosecWidely used for treatment worldwidePeptic ulcerandHelicobacter pylori infectionAfter digestive tract diseases, it reached a peak of 6.26 billion US dollars in 2000.Under the temptation of rich returns,Multinational pharmaceutical enterprisesLansoprazole, rabeprazolePantoprazoleA series of "peers" have formed a thriving proton pump inhibitor market
Following omeprazole, pantoprazole, lansoprazole, rabeprazole and esomeprazole have entered the global marketdomestic market, tenaprazoleLeminoprazole、EsalazoleAnd dithioprazole are new varieties under development.
2002, UKAstraZenecaThe company launchedReplacement productsEsomeprazole took the lead in August of the same yearSwedenListing,Trade nameIt is "Nexium".This drug is the first proton pump inhibitor produced by oxidation synthesis technology in the world, which has beenNobel Prize。Esomeprazole is also globalGrowth rateAs the fastest proton pump inhibitor product, Nexium's sales in the world's seven major prescription drug markets in 2005 were 4.633 billion US dollars. In 2006, the sales increased by 11.85% year on year, reaching 5.182 billion US dollars.
In 2003, Esomeprazole of AstraZeneca Sweden was sold under the trade name“nexium ”After listing in China,market shareIt has soared and became one of the sample hospitals in China in 2006growth rateThe highest variety, increased by 163.62% year on year, and exceeded 50 million yuanthe highest level。As the S – enantiomer of omeprazole, it has strong substitutability between the two, thus becoming a new drug of Losec.
However, the impact of pantoprazole, rabeprazole and lansoprazole on the market also encroached on the territory of Losec (omeprazole) and Nike. Therefore,AstraZenecaIt is impossible to recover the monopoly of the proton pump inhibitor market by Losec at the end of last century.
Losec: Scenery no longer exists
Omeprazole is the first proton pump inhibitor on the marketHydrogen ion、Potassium ionTransferred ATPase inhibitory anti ulcer drugs.Sweden in 1988Astellas Pharma The company was successfully developed, with the trade name "Antra" in theSwitzerlandGo public first.Passed in 1989FDAAfter approval, it is marketed in the United States for the treatment of ZES andreflux esophagitis, whose trade name is "Losec", is one of the main varieties of AstraZeneca.From the launch of the product to the middle and late 1990s, Losec has become one of the largest prescription drugs in the worlddigestive systemAnother milestone in medicine.
Losec'sAPIThe patent expired in April 1999, and the Prelosec produced and sold in the United States also expired on April 1, 2001. However, in view of its proprietary prescription, the United States extended its patent for several years.
With the expiration of Losec's patent, its market shareEurope and AmericaThe scenery is no longer beautiful after being nibbled.After successive declines in performance, in 2006, the global Losec market fell by 17% year on year, to only $1.371 billion.In 2000, Losec successively worked in Sweden, the United StatesMexicoConvert toOTC drugsOn December 31, 2004, Losec was officially approved as an OTC drug in China.
The development of omeprazole in China was relatively early, and SFDA approved it in 1992HainanHailing Pharmaceutical, Hainan SanyePharmaceutical factoryChangchun Beihua Pharmaceutical produces omeprazole 20mgEnteric coated capsulesFrom 1993 to 1995, Yalai was approved（Foshan）Pharmaceutical, Xi'anLijun Pharmaceutical、ShenyangThe products of Aohua Pharmaceutical, AstraZeneca (Wuxi), Guangdong Bidi Pharmaceutical and other enterprises are listed.product development Rapid abnormality, omeprazole APIomeprazole sodium APIs and capsulesEnteric coated tablet, enteric coated capsulesPelletAnd injection formulations have been successfully developed.
In 2004, HassleLakemedelAB, SwedenLosec MUPSTablets in ChinaAdministrative protectionAfter that, more than 100 enterprises in China successively applied for 260 acceptance numbers.By August 2013, SFDA had issued omeprazole andomeprazole sodium There are 20 production documents and 219 preparation documents of API.
According to statistical data, in 2005, the drug use amount of Losec in domestic sample hospitals was 320.1910 million yuan, an increase of 25.51% over the previous year. The national omeprazole market was driven by it, accounting for stomach medicineTotal sales43.29%, an increase of 2.33 over the previous yearPercentage point, expectedNational marketAbout 2.2 billion to 2.5 billion yuan.
After entering 2006,Market patternGreat changes are taking place, omeprazoleSimilar productsUnder the pressure of, the market share growth slowed down, especially in the first half of the year, the sales amount of omeprazole dropped significantly compared with the same period in 2005, becoming the only product with negative growth in the proton pump inhibitor category. The annual market share growth ended at 322.9769 million yuan, only 0.87% higher than the previous year,Its proportion in the five major proton pump inhibitors has dropped from 67.24% the previous year to 57.94%.
After analyzing the reason, it is estimated that after the launch of Losec as an OTC product, the market focus shifted relatively, giving up a part of the market to the new product, Nike, which has greatly improved in the sample hospitals, but domestic omeprazole failed to follow up in time.On the other hand, China'sretail marketThe main products that sell well are those with good quality and low price.Although Losec entered the Chinese OTC marketGreat expectations However, the road of Losec OTC is not as smooth as that of opening up the hospital market in 2006.
Among the sample hospitals, the growth rate of AstraZeneca's Losec is 17%, and that of Jiangsu Aosaikang Pharmaceutical Co., LtdOmeprazole Sodium for InjectionYear on year growth11.68%, ShandongLunan PharmaceuticalShares grew rapidly, up 15.17% year on year, while other brands of omeprazole grew slowly. Affected by the price reduction of drugs, sales increased but sales declined.
Lansoprazole: domestic product slightly wins
Lansoprazole
Lansoprazole is an upgraded product of omeprazole, which was successfully developed by Takeda Company in 1991.In May 1995, it was approved by FDA and listed in the United States with the trade name of "Prevacid".In 2005, Takeda, Tap Pharmaceutical, WyethAbbottThe sales of the four companies in the world's seven major pharmaceutical markets have reached 4.526 billion US dollars. In 2006, they were rated as one of the world's top ten best-selling drugs by Forbes magazine.
Lansoprazole is a new drug that inhibits gastric acid secretion. Its structural characteristics areSide chainImport influorineReplacement of elementsBenzimidazoleCompound, make itBioavailabilityIt is more than 30% higher than omeprazoleHelicobacter pyloriIts antibacterial activity was 4 times higher than omeprazole.
Lansoprazole API of Takeda Company of Japan and itsCapsuleAdministrative protection was granted in China on October 25, 1993 and expired on December 3, 2001.The patent in the United States also expired in July 2004.Lansoprazole was successfully copied in China in the mid-1990s,Shantou Special Economic ZoneBin Pharmaceutical Factory obtained the production approval of API and 15mg enteric coated tablets in 1998“Lanzido”Listing.By August 2007, SFDA had approved 37 API production approvals and 12 varieties of tablets, capsules and enteric coated tablets.
In 2006, the use of lansoprazole in sample hospitals in key cities in China increased by 25.49% year on year, and the amount of drug use exceeded 20 million yuan.GuangdongShantou Tuo"Lanzido" of Binhai Pharmaceutical Factory occupies the first place with 47.15% market share.Takeda Pharmaceutical Industry Co., Ltd. and Tianjin Takeda Pharmaceutical“Dakplon”It ranked second, accounting for 45.64% of the overall market."Lan Yixin" of Hainan Yier Pharmaceutical and Taiwan NanguangChemical pharmacysharesThe proportion of "cable detachment" is relatively small.
Pantoprazole: equal
Pantoprazole
Pantoprazole is the third proton pump inhibitor listed in the world after omeprazole and lansoprazole.The drug has high selectivity and bioavailability, and is recognized by doctors and patients with high safety in clinical treatment, thus promotingProduct marketGrowth.In 2006, it ranked second among the anti peptic ulcer drugs used in sample hospitals, accounting for 23.62% of the market share of proton pump inhibitors, and the amount of drug use increased by 31.71% year on year.
Pantoprazole was established in October 1994 by BykGulden Pharmaceutical Co., LtdSouth AfricaFirst time marketed drugs.Pantoprazole was listed in the top 500 drugs in the world's seven major drug markets, mainly GermanyAltena(Altana) PantozolWyethThere are 4 varieties in total, namely Protonix from Schwarz, Germany, Rifunc, and Peptazole/Ulcotenal from Ouhui, Italy. The sales in 2005 totaled 3.546 billion dollars, an average increase of 10.74% over the previous year.
Pantoprazole was successfully copied in China in 1998, and Shenyang Dongyu Pharmaceutical was the first to obtain the production approval issued by SFDA in 1999Jiangsu Yangzijiang PharmaceuticalNanjing Chang'ao Pharmaceutical Co., LtdDalianMeiluoda Pharmaceutical Co., Ltd., Hunan Jianlang Pharmaceutical Co., Ltd. and Shandong Lvye Pharmaceutical Co., Ltd. also obtained production approval documents.
Pantoprazole sodium Powder injectionAdministrative protection was obtained in China on December 30, 1998, and the period of administrative protection also ended after the expiration of the relevant patent EP0166287 on June 10, 2005.So far, SFDA has approved 10 producers of API, 4 producers of enteric coated tablets, 7 producers of enteric coated capsules, and 47 producersBaypen Preparations.In 2006, 13 manufacturers of pantoprazole entered the sample hospitals, and the total amount of medication has exceeded 100 million yuan.Jiangsu Yangzijiang Pharmaceutical Group"Weidi" and other 10 brands accounted for 53% of the total market, while the joint-venture or foreign-funded products of Hangzhou Zhongmei Huadong Pharmaceutical Co., LtdPanlisu, Baxter and Altenar PharmaceuticalsPantolokIt accounts for 47% of the overall market, forming a pattern of equal distribution in China.
Rabeprazole is an antiSecretory actionOfreversibilityThe proton pump inhibitor has a high PKaA value, and its anti secretory activity in vitro is 2~10 times stronger than omeprazole. Oral administration can quickly activate in vivo and play an acid inhibitory role in combination with the proton pump.Rabeprazole was developed and marketed by Japan Eisai in December 1998. Its tablet was approved by SFDA in February 2000, and its trade name is“Pollitt”The patent expires in May 2013.
After Rabeprazole was approved for listing in China, in order to quickly open the market situation of proton pump inhibitors in China, Eisai wanted to useXi'an JanssenstayGastrointestinal DiseasesThe strong advantage in drug sales was the strong launch of rabeprazole in China in September 2001 jointly with Xi'an Janssen. According to market monitoring data, this cooperation was still continuing in 2006.SFDA has approved 5 enterprises such as Jiangsu Haosen Pharmaceutical to produce API, in addition, 6 preparations have also been approved for production and listing.
In the rapidly growing proton pump inhibitor market, the growth rate of rabeprazole is only second to esomeprazole. In 2006, the drug use in sample hospitals increased by 58.76% year on year, and the annual drug use amount has exceeded 30 million yuan.Among them, the top five manufacturers in domestic sales accounted for 53.02% of the market, while Japanese Eisai accounted for 46.98% of the market.
