Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome(AIDS)patients has remained contentious,with conjectures pointing towards its correlation with distinct antiviral regimes.Prote...Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome(AIDS)patients has remained contentious,with conjectures pointing towards its correlation with distinct antiviral regimes.Protease inhibitors(PIs)stand as a prominent class of antiviral agents frequently utilized in AIDS management and have been significantly linked to premature senescence.This study aimed to investigate whether PI-containing regimens would accelerate osteoarthritis(OA)development and explore the molecular mechanisms underlying this association.A retrospective cohort of 151 HIV-infected individuals,categorized into PI and non-PI groups,was established.Patients in PI group exhibited lower KOOS and a higher prevalence of radiological knee OA than those in non-PI group.Additionally,25 anti-HIV drugs were screened and among all antiviral drugs,lopinavir had the most detrimental impact on cartilage anabolism,accelerating cartilage senescence and promoting mouse OA development.Mechanistically,lopinavir accelerated cellular senescence by inhibiting Zmpste24 and interfering nuclear membrane stability,which leads to decreased binding between nuclear membrane-binding protein Usp7 and Mdm2 and activates Usp7/Mdm2/p53 pathway.Zmpste24 overexpression reduces OA severity in mice.These findings suggest that PI-containing regimens accelerate cartilage senescence and OA development through Zmpste24 inhibition,which provides new insights into the selection of HIV regimens.展开更多
A fast,reliable,and cost-effective liquid chromatography-tandem mass spectrometry method was established to determine the effects of the traditional Chinese medicine employed to treat coronavirus disease 2019,namely,L...A fast,reliable,and cost-effective liquid chromatography-tandem mass spectrometry method was established to determine the effects of the traditional Chinese medicine employed to treat coronavirus disease 2019,namely,Lianhua Qingwen granules,Huoxiang Zhengqi capsules,Jinhua Qinggan granules,Shufeng Jiedu capsules,and Angong Niuhuang pills,on the pharmacokinetics of lopinavir/ritonavir in rats.Blood samples were prepared using the protein precipitation method and atazanavir was selected as the internal standard(IS).Separation was performed on an Agilent ZORBAX eclipse plus C18(2.1 mm×50 mm,1.8 μm)column using acetonitrile and water containing 0.1%formic acid as the mobile phase for gradient elution.The flow rate was 0.4 mL/min and the injection volume was 2 μL.Agilent Jet Stream electrospray ionization was used for mass spectrometry detection under positive ion multiple reaction monitoring mode at a transition of m/z 629.3→447.3 for lopinavir,m/z 721.3→296.1 for ritonavir,and m/z 705.4→168.1 for the IS.The method showed good linearity in the concentration range of 25→2500 ng/mL(r=0.9981)for lopinavir and 5e500 ng/mL(r=0.9984)for ritonavir.The intra-day and inter-day precision and accuracy were both within±15%.Items,such as dilution reliability and residual effect,were also within the acceptable limits.The method was used to determine the effects of five types of traditional Chinese medicines on the pharmacokinetics of lopinavir/ritonavir in rats.The pharmacokinetic results showed that the half-life of ritonavir in the groups administered Lianhua Qingwen granules and Huoxiang Zhengqi capsules combined with lopinavir/ritonavir was prolonged by approximately 1.5-to 2-fold relative to that in the control group.Similarly,the pharmacokinetic parameters of lopinavir were altered.Overall,the results of this study offer important theoretical parameters for the effective clinical use of five types of traditional Chinese medicines combined with lopinavir/ritonavir to reduce the occurrence of clinical adverse reactions.展开更多
Wuhan novel coronavirus or 2019-novel coronavirus(2019-nCoV)infection is a rapidly emerging respiratory viral disease[1].2019-nCoV infection is characterized as febrile illness with possible severe lung complication[1...Wuhan novel coronavirus or 2019-novel coronavirus(2019-nCoV)infection is a rapidly emerging respiratory viral disease[1].2019-nCoV infection is characterized as febrile illness with possible severe lung complication[1].The disease was firstly reported in China in December 2019 and then spread to many countries(such as Thailand,Japan and Singapore)[2,3].As a new disease,there is a limited knowledge of treatment for the infection.Lu recently proposed that some drug might be useful in treatment of 2019-nCoV infection[3].展开更多
Antiretroviral therapy in HIV patients is known for its negative effect on the cardiovascular system. One of the major adverse events in patients on lopinavir is increasing lipids. Hyperlipidaemia together with chroni...Antiretroviral therapy in HIV patients is known for its negative effect on the cardiovascular system. One of the major adverse events in patients on lopinavir is increasing lipids. Hyperlipidaemia together with chronic inflammation by HIV-infection itself makes these patients prone for cardiovascular diseases.The purpose of this study (a sub study within the FREE-study) was to determine if higher plasma lopinavir (LPV) concentrations lead to increase of serum lipids. Plasma drug concentrations were analysed up to week 24 in a prospective cohort of HIV antiretroviral therapy naive patients who started on a regimen of zidovudine, lamivudine and ritonavir-boosted lopinavir (FREE study). Prospectively we measured plasma lopinavir concentrations from baseline to week 24 in 72 naive HIV-patients starting on lopinavir (59 males and 13 females). A total of 210 samples were analysed, with at least 2 samples in every patient. Mean LPV trough concentration was 4.3 mg/L (± 2.1). The median intra-subject variation in LPV level was 38% (range 4% - 111%). Serum lipids were not correlated to LPV plasma concentrations possibly due to the wide intra-individual variability in LPV trough levels. Monitoring of plasma lopinavir and subsequent dose adjustment of LPV will not be useful to prevent hyperlipidaemia in HIV-patients treated with lopinavir.展开更多
Objective: The purpose of this study was to investigate whether switching HIV-infected patients stabilized on Trizivir (abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg) plus lopinavir/ritonavir 400 mg/100mg twice ...Objective: The purpose of this study was to investigate whether switching HIV-infected patients stabilized on Trizivir (abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg) plus lopinavir/ritonavir 400 mg/100mg twice daily to Trizivir alone affects clinical efficacy and tolerability. Methods: This phase 4, open-label, pilot study was conducted over 96 weeks in 23 antiretroviral-na?ve, HIV-infected patients. Initially, these patients received induction therapy with Trizivir plus lopinavir/ritonavir 400 mg/100mg twice daily. Patients who achieved a viral load 3. Nineteen patients completed induction;of the four who did not, three were lost to follow-up and one withdrew due to gastrointestinal adverse events. In 14 induction completers who had viral load measurements taken at week 48, intent-to-treat: observed analysis showed a week 48 viral load 3 higher than the baseline count. Twelve patients completed the subsequent 48-week Trizivir-alone maintenance phase, of whom 11 (92%) achieved viral loads of both 3 above baseline. Trizivir-only maintenance was associated with fewer adverse events than the Trizivir-lopinavir/ritonavir induction phase and with improvement in total cholesterol, LDL-cholesterol, and triglycerides. Conclusions: Trizivir-alone maintenance after Trizivir-lopinavir/ritonavir induction maintained virologic and CD4+ cell response, and was associated with an improved adverse event and lipid profile.展开更多
<p> Lopinavir is an antiretroviral of the protease inhibitor class (Figure 1 <span style="display:none;" id="__kindeditor_bookmark_end_3__"></span>and Figure 2). It is used agains...<p> Lopinavir is an antiretroviral of the protease inhibitor class (Figure 1 <span style="display:none;" id="__kindeditor_bookmark_end_3__"></span>and Figure 2). It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir). In the current research, the stimulated ATR-FTIR biospectroscopy of liquid sample of Lopinavir was investigated. The stimulated ATR-FTIR diffractions emitted through focusing the second harmonic laser beam Nd:YAG into the sample were recorded by Echelle spectrometer and ICCD detector. Increasing the energy of laser beam from 2.6 (mJ) to 16 (mJ) led to increase in stimulated ATR-FTIR signal but after breakdown threshold of liquid sample, further increasing energy led to the decrease in stimulating ATR-FTIR signals and for energies higher than 20 (mJ), they were disappeared. </p>展开更多
HIV/AIDS has been one of the most devastating global diseases. HIV-1 protease proteolytic action is responsible for the manufacture of grown, infectious species, consequently HIV-1 protease has become an attractive go...HIV/AIDS has been one of the most devastating global diseases. HIV-1 protease proteolytic action is responsible for the manufacture of grown, infectious species, consequently HIV-1 protease has become an attractive goal in the treatment and therapy of HIV. Several HIV-1 protease inhibitors based therapeutic agents are under investigation or currently in the market. Lopinavir (ABT-378) has a great value in this research field. Therefore, different methods have appeared aiming to develop efficient analogs by the utilization of variable techniques, since Lopinavir had showed low bioavailability when being prescribed alone, and various side effects after the combination of Lopinavir with another HIV-1 inhibitors such as Ritonavir, which is available in the markets nowadays under the brand name Kaletra. Replacement of the hydroxyethylene moiety in Lopinavir structure, which is responsible for the monohydroxylated metabolites with the stable to hydrolysis phosphinic group has been considered, since that hydroxyl group in the central core is responsible for the interaction with the carboxylic acid in the catalytic aspartyl residue of HIV-1 by hydrogen bonding and consequently supports the drug affinity to the protease. The small scale processes for the synthetic strategies for the new candidate phosphinic analog of Lopinavir protease inhibitor (PL1) is presented here in along with some preliminary pharmacological data.展开更多
Objective:To systematically evaluate the efficacy and safety of lopinavir/ritonavir(LPV/r)in the treatment of COVID-19.Methods:PubMed,Embase,Ovid,CNKI,CBM,Wanfang,and VIP databases were searched to obtain the clinical...Objective:To systematically evaluate the efficacy and safety of lopinavir/ritonavir(LPV/r)in the treatment of COVID-19.Methods:PubMed,Embase,Ovid,CNKI,CBM,Wanfang,and VIP databases were searched to obtain the clinical studies of LPV/r in the treatment of COVID-19 from December 2019 to July 2020.The literatures were screened according to the inclusion and exclusion criteria.Their qualities were evaluated according to the Newcastle-Ottawa Scale(NOS)and RevMan 5.3 software was used for meta-analysis.Results:A total of 688 patients were included in five studies,involving China and France.Compared with patients in the control group,who was only treated with routine treatment,there were no significant differences of the 7-day nucleic acid negative conversion rate and 14-day nucleic acid negative conversion rate in the treatment group.However,the use of LPV/r increased the incidence of adverse reactions in the treatment group compared to the control group.Conclusion:There is no available evidence to support the use of Lopinavir/ritonavir in the treatment of COVID-19.展开更多
High performance liquid chromatography was coupled with UV detection for simultaneous quantification of lopinavir （LPV） and ritonavir （RTV） in human plasma. This assay was sensitive, accurate and simple, and only ...High performance liquid chromatography was coupled with UV detection for simultaneous quantification of lopinavir （LPV） and ritonavir （RTV） in human plasma. This assay was sensitive, accurate and simple, and only used 200μL of plasma sample. Samples were liquid-liquid extracted, and diazepam was used as an internal standard. The chromatographic separation was achieved on a C18 reversed-phase analytic column with a mobile phase of acetonitrile-sodium dihydrogen phosphate buffer （10 mmol L-1, pH 4.80） （60：40, v/v）. UV detection was conducted at 205 nm and the column oven was set at 40℃. Calibration curves were constructed between 0,5-20 μg mL-1 for LPV and 0.05-5 μg mL-1 for RTV. The relative standard deviations were 2.16%-3.20% for LPV and 2.12%-2.60% for RTV for intra-day analysis, and 2.34%-4.04% for LPV and 0.31%-4.94% for RTV for inter-day analysis. The accuracy was within 100%＋10%. The mean extraction recoveries were 79.17%, 52.26% and 91.35% for RTV, LPV and diazepam, respectively. This method was successfully applied to human plasma samples from patients orally administered a salvage regimen of lopinavir-ritonavir tablets.展开更多
基金supported by Natural Science Foundation of China(82472476)Fundamental Research Funds for the Central Universities(YG2023ZD15)+2 种基金The Youth Talent Program from Shanghai Health System(2022YQ020)AI-Driven Reform of Research Paradigms Empowers Discipline Advancement Initiatives from Shanghai Municipal Education Commission(Grant No.JWAIZD-7)the Natural Science Foundation of Shanghai(23ZR1437300).
文摘Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome(AIDS)patients has remained contentious,with conjectures pointing towards its correlation with distinct antiviral regimes.Protease inhibitors(PIs)stand as a prominent class of antiviral agents frequently utilized in AIDS management and have been significantly linked to premature senescence.This study aimed to investigate whether PI-containing regimens would accelerate osteoarthritis(OA)development and explore the molecular mechanisms underlying this association.A retrospective cohort of 151 HIV-infected individuals,categorized into PI and non-PI groups,was established.Patients in PI group exhibited lower KOOS and a higher prevalence of radiological knee OA than those in non-PI group.Additionally,25 anti-HIV drugs were screened and among all antiviral drugs,lopinavir had the most detrimental impact on cartilage anabolism,accelerating cartilage senescence and promoting mouse OA development.Mechanistically,lopinavir accelerated cellular senescence by inhibiting Zmpste24 and interfering nuclear membrane stability,which leads to decreased binding between nuclear membrane-binding protein Usp7 and Mdm2 and activates Usp7/Mdm2/p53 pathway.Zmpste24 overexpression reduces OA severity in mice.These findings suggest that PI-containing regimens accelerate cartilage senescence and OA development through Zmpste24 inhibition,which provides new insights into the selection of HIV regimens.
基金supported by the Development Plan of Science and Technology of Traditional Chinese Medicine in Shandong Province(Grant No.:2019e0350)the Development Plan of Medical and Health Technology in Shandong Province(Grant No.:2018WS133).
文摘A fast,reliable,and cost-effective liquid chromatography-tandem mass spectrometry method was established to determine the effects of the traditional Chinese medicine employed to treat coronavirus disease 2019,namely,Lianhua Qingwen granules,Huoxiang Zhengqi capsules,Jinhua Qinggan granules,Shufeng Jiedu capsules,and Angong Niuhuang pills,on the pharmacokinetics of lopinavir/ritonavir in rats.Blood samples were prepared using the protein precipitation method and atazanavir was selected as the internal standard(IS).Separation was performed on an Agilent ZORBAX eclipse plus C18(2.1 mm×50 mm,1.8 μm)column using acetonitrile and water containing 0.1%formic acid as the mobile phase for gradient elution.The flow rate was 0.4 mL/min and the injection volume was 2 μL.Agilent Jet Stream electrospray ionization was used for mass spectrometry detection under positive ion multiple reaction monitoring mode at a transition of m/z 629.3→447.3 for lopinavir,m/z 721.3→296.1 for ritonavir,and m/z 705.4→168.1 for the IS.The method showed good linearity in the concentration range of 25→2500 ng/mL(r=0.9981)for lopinavir and 5e500 ng/mL(r=0.9984)for ritonavir.The intra-day and inter-day precision and accuracy were both within±15%.Items,such as dilution reliability and residual effect,were also within the acceptable limits.The method was used to determine the effects of five types of traditional Chinese medicines on the pharmacokinetics of lopinavir/ritonavir in rats.The pharmacokinetic results showed that the half-life of ritonavir in the groups administered Lianhua Qingwen granules and Huoxiang Zhengqi capsules combined with lopinavir/ritonavir was prolonged by approximately 1.5-to 2-fold relative to that in the control group.Similarly,the pharmacokinetic parameters of lopinavir were altered.Overall,the results of this study offer important theoretical parameters for the effective clinical use of five types of traditional Chinese medicines combined with lopinavir/ritonavir to reduce the occurrence of clinical adverse reactions.
文摘Wuhan novel coronavirus or 2019-novel coronavirus(2019-nCoV)infection is a rapidly emerging respiratory viral disease[1].2019-nCoV infection is characterized as febrile illness with possible severe lung complication[1].The disease was firstly reported in China in December 2019 and then spread to many countries(such as Thailand,Japan and Singapore)[2,3].As a new disease,there is a limited knowledge of treatment for the infection.Lu recently proposed that some drug might be useful in treatment of 2019-nCoV infection[3].
文摘Antiretroviral therapy in HIV patients is known for its negative effect on the cardiovascular system. One of the major adverse events in patients on lopinavir is increasing lipids. Hyperlipidaemia together with chronic inflammation by HIV-infection itself makes these patients prone for cardiovascular diseases.The purpose of this study (a sub study within the FREE-study) was to determine if higher plasma lopinavir (LPV) concentrations lead to increase of serum lipids. Plasma drug concentrations were analysed up to week 24 in a prospective cohort of HIV antiretroviral therapy naive patients who started on a regimen of zidovudine, lamivudine and ritonavir-boosted lopinavir (FREE study). Prospectively we measured plasma lopinavir concentrations from baseline to week 24 in 72 naive HIV-patients starting on lopinavir (59 males and 13 females). A total of 210 samples were analysed, with at least 2 samples in every patient. Mean LPV trough concentration was 4.3 mg/L (± 2.1). The median intra-subject variation in LPV level was 38% (range 4% - 111%). Serum lipids were not correlated to LPV plasma concentrations possibly due to the wide intra-individual variability in LPV trough levels. Monitoring of plasma lopinavir and subsequent dose adjustment of LPV will not be useful to prevent hyperlipidaemia in HIV-patients treated with lopinavir.
文摘Objective: The purpose of this study was to investigate whether switching HIV-infected patients stabilized on Trizivir (abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg) plus lopinavir/ritonavir 400 mg/100mg twice daily to Trizivir alone affects clinical efficacy and tolerability. Methods: This phase 4, open-label, pilot study was conducted over 96 weeks in 23 antiretroviral-na?ve, HIV-infected patients. Initially, these patients received induction therapy with Trizivir plus lopinavir/ritonavir 400 mg/100mg twice daily. Patients who achieved a viral load 3. Nineteen patients completed induction;of the four who did not, three were lost to follow-up and one withdrew due to gastrointestinal adverse events. In 14 induction completers who had viral load measurements taken at week 48, intent-to-treat: observed analysis showed a week 48 viral load 3 higher than the baseline count. Twelve patients completed the subsequent 48-week Trizivir-alone maintenance phase, of whom 11 (92%) achieved viral loads of both 3 above baseline. Trizivir-only maintenance was associated with fewer adverse events than the Trizivir-lopinavir/ritonavir induction phase and with improvement in total cholesterol, LDL-cholesterol, and triglycerides. Conclusions: Trizivir-alone maintenance after Trizivir-lopinavir/ritonavir induction maintained virologic and CD4+ cell response, and was associated with an improved adverse event and lipid profile.
文摘<p> Lopinavir is an antiretroviral of the protease inhibitor class (Figure 1 <span style="display:none;" id="__kindeditor_bookmark_end_3__"></span>and Figure 2). It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir). In the current research, the stimulated ATR-FTIR biospectroscopy of liquid sample of Lopinavir was investigated. The stimulated ATR-FTIR diffractions emitted through focusing the second harmonic laser beam Nd:YAG into the sample were recorded by Echelle spectrometer and ICCD detector. Increasing the energy of laser beam from 2.6 (mJ) to 16 (mJ) led to increase in stimulated ATR-FTIR signal but after breakdown threshold of liquid sample, further increasing energy led to the decrease in stimulating ATR-FTIR signals and for energies higher than 20 (mJ), they were disappeared. </p>
文摘HIV/AIDS has been one of the most devastating global diseases. HIV-1 protease proteolytic action is responsible for the manufacture of grown, infectious species, consequently HIV-1 protease has become an attractive goal in the treatment and therapy of HIV. Several HIV-1 protease inhibitors based therapeutic agents are under investigation or currently in the market. Lopinavir (ABT-378) has a great value in this research field. Therefore, different methods have appeared aiming to develop efficient analogs by the utilization of variable techniques, since Lopinavir had showed low bioavailability when being prescribed alone, and various side effects after the combination of Lopinavir with another HIV-1 inhibitors such as Ritonavir, which is available in the markets nowadays under the brand name Kaletra. Replacement of the hydroxyethylene moiety in Lopinavir structure, which is responsible for the monohydroxylated metabolites with the stable to hydrolysis phosphinic group has been considered, since that hydroxyl group in the central core is responsible for the interaction with the carboxylic acid in the catalytic aspartyl residue of HIV-1 by hydrogen bonding and consequently supports the drug affinity to the protease. The small scale processes for the synthetic strategies for the new candidate phosphinic analog of Lopinavir protease inhibitor (PL1) is presented here in along with some preliminary pharmacological data.
文摘Objective:To systematically evaluate the efficacy and safety of lopinavir/ritonavir(LPV/r)in the treatment of COVID-19.Methods:PubMed,Embase,Ovid,CNKI,CBM,Wanfang,and VIP databases were searched to obtain the clinical studies of LPV/r in the treatment of COVID-19 from December 2019 to July 2020.The literatures were screened according to the inclusion and exclusion criteria.Their qualities were evaluated according to the Newcastle-Ottawa Scale(NOS)and RevMan 5.3 software was used for meta-analysis.Results:A total of 688 patients were included in five studies,involving China and France.Compared with patients in the control group,who was only treated with routine treatment,there were no significant differences of the 7-day nucleic acid negative conversion rate and 14-day nucleic acid negative conversion rate in the treatment group.However,the use of LPV/r increased the incidence of adverse reactions in the treatment group compared to the control group.Conclusion:There is no available evidence to support the use of Lopinavir/ritonavir in the treatment of COVID-19.
基金supported by the National Key Technologies R&D Program for the 11th Five-year Plan (Grant No. 2008ZX10001-006)the Key Clinical Program of the Ministry of Health 2010-2012
文摘High performance liquid chromatography was coupled with UV detection for simultaneous quantification of lopinavir （LPV） and ritonavir （RTV） in human plasma. This assay was sensitive, accurate and simple, and only used 200μL of plasma sample. Samples were liquid-liquid extracted, and diazepam was used as an internal standard. The chromatographic separation was achieved on a C18 reversed-phase analytic column with a mobile phase of acetonitrile-sodium dihydrogen phosphate buffer （10 mmol L-1, pH 4.80） （60：40, v/v）. UV detection was conducted at 205 nm and the column oven was set at 40℃. Calibration curves were constructed between 0,5-20 μg mL-1 for LPV and 0.05-5 μg mL-1 for RTV. The relative standard deviations were 2.16%-3.20% for LPV and 2.12%-2.60% for RTV for intra-day analysis, and 2.34%-4.04% for LPV and 0.31%-4.94% for RTV for inter-day analysis. The accuracy was within 100%＋10%. The mean extraction recoveries were 79.17%, 52.26% and 91.35% for RTV, LPV and diazepam, respectively. This method was successfully applied to human plasma samples from patients orally administered a salvage regimen of lopinavir-ritonavir tablets.
