江苏省某胸部专科医院肺癌治疗的原研药与仿制药利用分析

目的：在加速仿制药替代的背景下,提出促进仿制药使用的政策建议。方法：选取江苏省某胸部专科医院治疗肺癌的8种既有原研药也有仿制药的品种,按季度分析2018年1月至2020年6月原研药和仿制药使用量占比、使用金额占比、价格比,以及2019年6月至2020年6月执行集中采购前后仿制药替代潜在的费用节省率。结果：2018年第1季度至2020年第2季度,原研药、仿制药使用数量占比分别由22.38%下降至14.26%、77.62%上升至85.87%,使用金额占比分别由39.43％下降至21.56％、60.57％上升至78.44％,仿制药与原研药价格比从2.08上升至2.75。在执行集中采购后,仿制药替代原研药潜在可节约费用1 061 254.51元,费用节省率为55.93％。结论：随着仿制药相关政策的推进,仿制药使用数量和金额占比都在上升,仿制药替代确有降低药品费用支出的作用。因此,加快仿制药一致性评价,同时配合仿制药政策的宣传,着力提高医患对仿制药的认同,再通过集中采购政策,可以促进仿制药利用以节约医疗资源。     

试点城市带量采购政策对某三级综合医院门诊心血管类原研药和仿制药利用状况的影响

目的 分析试点城市（4个直辖市和7个较大规模城市）（简称“4+7”城市）带量采购对心血管药物利用状况的影响,为仿制药替代原研药使用政策优化提供参考。方法 选择上海市某三级综合医院门诊治疗心血管疾病的11种既有仿制药也有原研药的药物,分析带量采购政策实施前（2018年4月1日至9月30日）及实施后（2019年4月1日至9月30日）仿制药和原研药使用量占比、使用金额占比、日费用比及仿制药替代原研药的潜在费用节省率。结果 带量采购政策实施后,原研药使用数量占比、使用金额占比分别由84.32%下降至58.12%、86.02%下降至78.16%;仿制药使用数量占比、使用金额占比分别由15.68%上升至41.88%、13.98%上升至21.84%,仿制药与原研药日费用比由0.87降至0.39。在疗效相同的条件下,政策实施前后仿制药替代原研药潜在可节省费用分别为337.03万元、333.99万元,费用节省率分别为35%、61%。结论 “4+7”带量采购政策大幅度增加了心血管类仿制药的使用数量,明显降低了药品费用;但对仿制药使用数量和金额占比影响较小,仍存在较大的费用节省空间。建议进一步加大仿制药替代原研药的政策宣传,加快仿制药一致性评价进程和采取措施避免原研药与仿制药价格差距的扩大。     

北京市85家二、三级公立医院心血管类原研药与仿制药利用分析

摘 要 目的：以心血管类药物为例,分析原研药和仿制药在公立医院的销售量、销售价格和销售金额,为促进仿制药的使用提供证据支持和提出政策建议。方法：从国家食品药品监督管理总局南方医药经济研究所医药数据库及北京市医药阳光采购综合管理平台提取数据,选择其中包含的北京市全部公立医院（共计85家二级和三级医院）的11种心血管类药物,分析2015年每种药物的原研药和仿制药销售量占比、销售金额占比、价格比和仿制药替代原研药的潜在费用节省率。结果：11种目标心血管类药物原研药与仿制药的平均销售金额占比分别为81.07%和18.93%;平均销售量占比分别为74.68%和25.32%;价格比在1.01~5.77之间,价格比平均值为2.09,中位数为1.61;仿制药替代原研药潜在可节省费用总计4.10亿元,费用节省率达59.21%。结论：11种目标心血管类药物的仿制药2015年在北京市二、三级公立医院中占有的市场份额很少。在公立医院中以质量和疗效有保障的仿制药替代原研药将节约大量药品费用。建议加快仿制药质量和疗效一致性评价,增强公众对仿制药质量和疗效的信心,以便尽快建立仿制药替代制度,通过医保支付配套政策鼓励仿制药的采购、处方和使用,以节省医药费用支出     

带量采购政策对苏北地区5家公立医院原研药和 仿制药临床使用的影响

目的:分析带量采购政策对苏北地区原研药和仿制药临床使用的影响,为促进仿制药的临床使用提供证据支持和政策建议.方法:选取该地区5家公立医院12种既有原研药又有仿制药的药品,对带量采购政策前(2019年上半年)及政策后(2020年上半年)原研药和仿制药使用数量、销售金额、仿制药替代率、实际费用节省及节省率等进行分析.结果:该政策实施后,仿制药的使用数量同比增长了39.64％,其销售金额下降了75.81％;仿制药替代率由42.43％上升至57.42％,目标药物实际节省费用1629.16万元,费用节省率为271.20％.结论:带量采购政策实施后,该地区仿制药使用数量大幅度上升,患者药品费用支出减少,切实减轻了部分患者用药负担.     

仿制药替代潜在最大费用节省研究

目的在仿制药替代背景下,比较原研药和仿制药的价格和采购量,测算仿制药替代的潜在最大费用节省,推动仿制药供应与使用。方法基于陕西省药品招标采购数据,选取2017年12月第一批通过仿制药质量和疗效一致性评价的17个品种(16个品规)药品,对其2017年至2018年的价格、采购量进行分析;采用成本分析法、推测预算法,对采购平台上该通用名、剂型的药品替换为通过仿制药质量和疗效一致性评价单价最低的仿制药,测算年均仿制药替代的潜在最大费用节省。结果价格由高到低依次为原研药、未通过一致性评价的仿制药、通过一致性评价的仿制药;采购量方面,5个品规药品的原研药采购量占比较高,11个品规药品的仿制药采购量占比较高,1个品规药品未发生仿制药替代;对16个品规药品进行仿制药替代后,测算出潜在最大费用节省为3243.63万元。结论仿制药替代可显著节省药品费用,我国的仿制药市场提升空间较大,后续应加快推进仿制药一致性评价和临床使用。     

"4+7城市"药品集中采购政策实施后,我院抗病毒原研药与采购药门诊的使用情况分析

目的 以抗病毒药恩替卡韦、富马酸替诺福韦二吡呋酯为例,分析"4+7城市"药品集中采购政策实施下原研药与采购药在门诊的使用情况.方法 选取2021年6月-11月,解放军总医院第五医学中心门诊库存系统数据对价格比、销售金额、采购药潜在节省费用以及使用数量等方面进行研究.结果 该院原研药平均销售金额占比为96.07％,采购药...     

“4＋7”带量采购对内蒙古自治区人民医院口服抗肿瘤药原研药和仿制药使用情况影响

目的 分析“4＋7”带量采购政策对内蒙古自治区人民医院口服抗肿瘤药品原研药和仿制药使用的影响，为临床药学服务和医院的药事管理提供依据。方法 采用Excel软件计算口服抗肿瘤药品的使用数量、金额、价格、用药频度（DDDs）、限定日费用（DDC）、占比、增幅、降幅，及仿制药替代率、费用节省率进行分析。结果 “4＋7”带量采购实施后，原研药和仿制药价格出现了不同幅度的降价，其中中选品种来曲唑单品价格降幅最大，降幅超过60%，原研药中价格降幅最大的是阿斯利康制药有限公司生产的吉非替尼，达30%。“4＋7”带量采购实施后，甲磺酸伊马替尼、替吉奥、来曲唑、阿那曲唑、卡培他滨、替莫唑胺仿制药DDDs均增加，而销售金额均下降。吉非替尼仿制药DDDs增幅最大，达74.17%，销售金额则增加57.38%。甲磺酸伊马替尼原研药受带量采购政策影响，DDDs和销售金额均增加，而其他相应的原研药的DDDs和销售金额均减少。“4＋7”带量采购的实施进一步提高仿制药的使用率，为医保费用节省899万元，费用节省率为49.99%。结论 带量政策实施后，药品费用支出减少，切实减轻了部分患者的用药负担。     

基于双重差分模型的药品集中采购对某院抗肿瘤药使用的影响

目的 从药物经济学角度评价国家组织药品集中采购政策对某院抗肿瘤原研药和仿制药使用的影响,并分析政策执行前后患者治疗的脱落情况。方法 调取我院和中国科学技术大学附属第一医院抗肿瘤药物的用药信息,时间为集中采购前后各一年。按照患者是否使用集中采购中选药品将其分为观察组和对照组,采用双重差分模型法分析药品成本、患者年次均药品费用、药品总使用金额、药品使用数量占比、药品使用金额占比、患者治疗脱落等方面对我院抗肿瘤类原研药和仿制药的使用情况的影响。结果 共纳入研究对象26 438人,口服抗肿瘤药品10种。政策实施后,观察组与对照组患者年次均药品费用降幅分别为58.3%和2.0%。药品总使用金额相比政策实施前减少了2 531.8万元,仿制药的使用数量提高了12.1%,使用金额提高了3.3%。政策实施后,年度患者治疗脱落人数占比下降10.7%。结论 在国家组织药品集中采购政策影响下,抗肿瘤仿制药价格大幅降低,而患者治疗依从性明显提高。但采购的药物品种规格较为单一,医疗机构过于重视相关临床使用指标考核,在一定程度上影响了用药需求的多样化。     

药品带量采购对某医院抗精神病药原研药和仿制药使用情况影响

目的：分析带量采购对抗精神病药品原研药和仿制药的使用情况影响,为政策制定和医院药事管理提供参考。方法：采用药物经济学方法对带量采购实施前后门诊药房抗精神病药品的数量、金额、用药频度（DDDs）、日均费用（DDC）、仿制药替代率、费用节省等进行分析。结果：带量采购政策实施后,抗精神病药中仿制药使用数量增加4%,仿制药使用金额降低3%。带量采购实施后包含带量采购中选品种的奥氮平片和利培酮片实际费用节省分别为547万元、252万元,占抗精神病药品总节省费用的85.9%,为医保费用节省501万元。结论：本次带量采购政策落地一年,一定程度上解决了药品价格虚高问题,切实降低了部分患者的用药负担,提升了医保基金的使用效率。     

国家药品集中采购前后陕西省原研与仿制降压药可负担性的横断面调查

目的 了解国家药品集中采购实施前后，陕西省高血压用药的可负担性。方法 以最低日工资标准和年人均可支配收入为指标，对2018年和2021年陕西省集中采购中标的10种仿制降压药和与其相同成分的原研降压药的可负担性进行横断面调查。结果 国家药品集中采购政策实施以来，陕西省10种原研和仿制降压药可负担性均有所改善。10种原研药和仿制药月药品支出分别由2018年最低日工资标准的1.86～4.54倍和0.09～2.19倍下降至2021年的0.61～3.21倍和0.03～0.94倍。陕西省城镇居民对于降压药的可负担性优于农村居民，仿制降压药的可负担性优于原研药。未参加医疗保险陕西省农村居民原研降压药年药品支出占其年人均可支配收入的比重由2018年的10.29%～25.10%下降至2021年的3.12%～16.34%;仿制药其比例由2018年的0.49%～12.11%下降至2021年的0.15%～4.78%;参加医疗保险农村居民原研降压药其比例由2018年的5.63%～10.81%下降到2021年的2.63%～7.26%,仿制药其比例由2018年的0.49%～6.27%下降到2021年的0.15%～3...     

Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro

[6,7-³H] Estrone (E) and [6,7-³H]estradiol-17 (E₂) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E₂ were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 g/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (mol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E₂, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E₂, respectively. The values for male hamster kidney were < 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate.Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 10³–10⁴ have been found for potent, 10² for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.Paper presented at the Satellite Symposium of the European Society of Toxicology, Rome, March 29, 1983     

Metabolic interaction between imipramine and carbamazepine in vivo and in vitro in rats

Summary The pharmacokinetic consequences of the combination of carbamazepine with imipramine in male Wistar rats have been investigated. It was found that a 2-week treatment with the combination resulted in the increase of the concentrations of the parent compounds and a simultaneous decrease in their metabolites in blood plasma i.e. carbamazepine inhibited imipramine demethylation in the side chain while imipramine inhibited carbamazepine 10,11-epoxidation. The velocity of imipramine 2-hydroxylation and 10,11-epoxy-carbamazepine hydration did not seem to be changed by the combination. On the basis of studies in vitro it is concluded that the observed metabolic interaction between carbamazepine and imipramine is due to the competition of the drugs for the active centre of cytochrome P 450 and to a certain qualitative alteration of the enzyme by imipramine as can be deducted from the decrease of carbamazepine binding to the cytochrome. Send offprint requests to K. J. Netter     

Nicotine metabolism and urinary elimination in mouse: in vitro and in vivo

This study aimed at elucidating the in vivo metabolism of nicotine both with and without inhibitors of nicotine metabolism. Second, the role of mouse CYP2A5 in nicotine oxidation in vitro was studied as such information is needed to assess whether the mouse is a suitable model for studying chemical inhibitors of the human CYP2A6. The oxidation of nicotine to cotinine was measured and the ability of various inhibitors to modify this reaction was determined. Nicotine and various inhibitors were co-administered to CD2F1 mice, and nicotine and urinary levels of nicotine and four metabolites were determined. In mouse liver microsomes anti-CYP2A5 antibody and known chemical inhibitors of the CYP2A5 enzyme blocked cotinine formation by 85-100%, depending on the pre-treatment of the mice. The amount of trans-3-hydroxycotine was five times higher than cotinine N-oxide, and ten times higher than nicotine N-1-oxide and cotinine. Methoxsalen, an irreversible inhibitor of CYP2A5, significantly reduced the metabolic elimination of nicotine in vivo, but the reversible inhibitors had no effect. It is concluded that the metabolism of nicotine in mouse is very similar to that in man and, therefore, that the mouse is a suitable model for testing novel chemical inhibitors of human CYP2A6.     

Arsenic induced changes in growth development and apoptosis in neonatal and adult brain cells in vivo and in tissue culture

Arsenic at a nonlethal level in drinking water consumed over a period of time has been reported to produce chronic toxicity and various types of health problems ranging from skin cancer to disturbance in memory. Neurotoxic effects have been reported in clinical cases with chronic exposure to arsenic. Physiological detoxication of arsenic occurs partially through methylation. Arsenic and its methylated derivatives are distributed in different organs and systems. The present study examined the possible interference in the neuronal development and differentiation due to the exposure to arsenic during gestation. The experiments were carried out to examine short and long term effects of arsenic on brain explants and cells grown and maintained in tissue culture system. The effects of arsenic exposure showed changes in brain cell membrane function indicated by generation and release of reactive oxygen-nitrogen intermediates. On the morphological aspect the explants' growth was reduced, ground matrix was lost and neural networking was inhibited. Cells showed signs of apoptotic changes. Arsenic toxicity may induce damage to brain cells prior to more visible clinical conditions. The deleterious effects also pass from the maternal to fetal tissue across the transplacental barrier.     

Penetration and action of edoxudine in vitro and in vivo

The penetration of 5-ethyl-2'-deoxyuridine (edoxudine, Aedurid) from gel base with and without the addition of urea and other adjuvant has been studied in an in vitro model using guinea pig skin. The formulation of 3% edoxudine gel with 5% urea showed the best results. In vivo experiments on hairless mice infected intracutaneously with herpes simplex virus type 1 also showed this formulation's good efficacy as compared to other formulations.     

Buprenorphine and naloxone alone and in combination in opioid-dependent humans

Subjective, physiological and behavioral effects of subcutaneously administered hydromorphone (6 mg), naloxone (0.2 mg), buprenorphine (0.2 and 0.3 mg), and two buprenorphine-naloxone combinations (buprenorphine 0.2 mg plus naloxone 0.2 mg and buprenorphine 0.3 mg plus naloxone 0.2 mg) were assessed under double-blind conditions in six opioid-dependent volunteers. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 120 min after drug administration. Hydromorphone decreased pupil diameter and respiration, increased blood pressure and increased scores on subjective measures indicating opioid-like effects. Buprenorphine given alone had no significant effect on any variable measured. Naloxone given alone produced opioid abstinence-like effects which were measurable on subject- and observer-rated behavioral measures and physiological measures. Buprenorphine in combination with naloxone somewhat attenuated the naloxone-precipitated withdrawal response. Overall, the naloxone-buprenorphine combinations produced effects which were qualitatively similar to the effects of naloxone alone, suggesting a low potential for abuse of the combination product by opioid-dependent individuals.Supported by a grant from Reckitt and Colman Pharmaceutical Division and USPHS Grants DA-00050 and DA-04089 from the National Institute on Drug Abuse     

Cadmium in milk and mammary gland in rats and mice

The purpose of the present investigation was to study the uptake of cadmium in mammary tissue, effects on milk secretion and composition, and lactational transport of cadmium to the sucklings. Cadmium exposure during lactation resulted in retention of cadmium in the mammary tissue in mice and rats. The uptake of cadmium in the mammary tissue was rapid, as shown in lactating mice by whole-body autoradiography 4 h after an intravenous injection of a tracer dose of (109)CdCl(2). Retention of cadmium in kidneys of suckling pups was observed in the autoradiograms at 7 days after exposure of the dams. Lactating rats were intravenously infused with (109)CdCl(2) in 0.9% saline via osmotic minipumps from day 3 to day 16 after parturition. The cadmium dose given was 0, 8.8, 62 and 300 microg Cd/kg body wt. per day. Plasma and milk were collected at day 10 and 16 after parturition. Plasma cadmium levels in dams increased from day 10 to day 16. Cadmium levels were higher in milk than in plasma, with milk/plasma ratios varying from 2 to 6. Zinc levels in milk were positively correlated to cadmium levels in milk (r(2)=0.26; P=0. 03). In milk, (109)Cd was distributed in fat (46-52%), casein fraction (40-46%), and whey fraction (6-8%). There was a high correlation between cadmium concentrations in pups' kidney and cadmium concentrations in dam's milk (r(2)=0.98; P < 0.001). Of the cadmium dose given to the dams <0.05% was retained in the litters on day 16 of lactation. No effects were observed due to cadmium exposure on body weight in pups or dams. Cadmium treatment did not cause any effect on the lactose or protein concentration in milk, the concentrations of DNA, RNA or the ratio RNA/DNA in the mammary gland. Histological evaluation of mammary tissue did not reveal any abnormalities at any dose level. (109)Cd was bound to metallothionein in mammary tissue. The fraction of radiolabelled cadmium bound to metallothionein increased in a dose-dependent manner in both the liver (88-98%) and mammary tissue (57-80%). The present results indicate a low transfer of cadmium to the suckling pup, which might be due to binding of cadmium to metallothionein in the mammary tissue. However, during the susceptible developmental period even a low cadmium exposure may be of concern.     

Nicotine metabolism and urinary elimination in mouse: in vitro and in vivo

This study aimed at elucidating the in vivo metabolism of nicotine both with and without inhibitors of nicotine metabolism. Second, the role of mouse CYP2A5 in nicotine oxidation in vitro was studied as such information is needed to assess whether the mouse is a suitable model for studying chemical inhibitors of the human CYP2A6. The oxidation of nicotine to cotinine was measured and the ability of various inhibitors to modify this reaction was determined. Nicotine and various inhibitors were co-administered to CD2F1 mice, and nicotine and urinary levels of nicotine and four metabolites were determined. In mouse liver microsomes anti-CYP2A5 antibody and known chemical inhibitors of the CYP2A5 enzyme blocked cotinine formation by 85–100%, depending on the pre-treatment of the mice. The amount of trans-3-hydroxycotine was five times higher than cotinine N-oxide, and ten times higher than nicotine N-1-oxide and cotinine. Methoxsalen, an irreversible inhibitor of CYP2A5, significantly reduced the metabolic elimination of nicotine in vivo, but the reversible inhibitors had no effect. It is concluded that the metabolism of nicotine in mouse is very similar to that in man and, therefore, that the mouse is a suitable model for testing novel chemical inhibitors of human CYP2A6.     

Circulating nucleic acids in plasma and serum: roles in diagnosis and prognosis in diabetes and cancer

The presence of DNA and RNA circulating in human plasma and serum is described. The possible sources of the DNA/RNA in blood, their ability to enter other cells and to express in the recipient cells are discussed and the relationship with metastases considered. The possible role(s) of the DNA/RNA in clinical diagnosis, in monitoring treatment and in prognosis are considered for diabetes and oncology.