Antiretroviral Protease Inhibitors Research Articles

Structural multiplicity in a solvated hydrate of the antiretroviral protease inhibitor Lopinavir

Lopinavir is a potent protease inhibitor that is used as a first-line pharmaceutical drug for the treatment of HIV. The multi-component solvated Lopinavir crystal, systematic name (2S)-N-[(2S,4S,5S)-5-[2-(2,6-dimethylphenoxy)acetamido]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide–ethane-1,2-diol–water (8/3/7) 8C37H48N4O5·3C2H6O2·7H2O, was prepared using evaporative methods. The crystalline material obtained from this experimental synthesis was characterized and elucidated by single-crystal X-ray diffraction (SC-XRD). The crystal structure is unusual in that the unit cell contains 18 molecules. The stoichiometric ratio of this crystal is eight Lopinavir molecules [8(C37H48N4O5)], three ethane-1,2-diol molecules [3(C2H6O2)] and seven water molecules [7(H2O)]. The crystal packing features both bi- and trifurcated hydrogen bonds between atoms.

The relationship between HIV/AIDS and coronary heart disease: A bibliometric analysis.

Acquired immunodeficiency syndrome is a malignant infectious disease caused by the human immunodeficiency virus (HIV). HIV gradually destroys the body's immune system and weakens the body's ability to resist diseases. People living with HIV may have a higher incidence of coronary heart disease than people without HIV. A literature retrieval from January 1, 1993 to October 1, 2023 based on the Web of Science Core Collection database. CiteSpace6.2.R4, VOSviewer v1.6.19, and Microsoft Excel 2019 were utilized for analyzing the following terms: countries, institutions, authors, journals, references, and keywords. There were 1144 articles. The highest number of articles is in the USA, followed by Italy. University of California System, Harvard University, and Johns Hopkins University were the top 3 most productive institutions with publications in this field of research. Journal of Infectious Diseases ranked first with the highest publications (532 records), followed by Immunology (362 records), and Cardiac Cardiovascular Systems (242 records). Keyword co-occurrence analysis showed antiretroviral therapy, myocardial infarction, and protease inhibitors, etc. Keyword cluster analysis obtained 13 categories, which were roughly divided into 3 themes: (1) cardiovascular disease that has occurred or may occur; (2) HIV acquisitions that have occurred; (3) risk factors for cardiovascular disease. The article obtained the hotspots and trends and provided references for subsequent research. Based on the keyword citation burst detection analysis, we speculated that heart failure, risk, subclinical atherosclerosis, infection, and association were the research hotspots in recent years, which had a certain predictive effect on the future research direction.

Lopinavir-Loaded Self-Nanoemulsifying Drug Delivery System for Enhanced Solubility: Development, Characterisation and Caco-2 Cell Uptake.

The antiretroviral protease inhibitor drug, lopinavir (LPV), is used to treat HIV-1 infection. LPV is known to have limited oral bioavailability, which may be attributed to its poor aqueous solubility, low efficacy and high first-pass metabolism. Self-nanoemulsifying drug delivery systems (SNEDDS) for LPV have been developed and optimised to counter the current issues. The titration method was used to prepare LPV-loaded SNEDDS (LPV-SNEDDS). Six different pseudo-ternary phase diagrams were constructed to identify the nanoemulsifying region. The developed formulations were chosen in terms of globule size < 100 nm, dispersity ≤ 0.5, dispersibility (Grade A) and% transmittance > 85. Heating-cooling cycle, freeze-thaw cycle, and centrifugation studies were performed to confirm the stability of the developed SNEDDS. The final LPV-SNEDDS (L-14) droplet size was 58.18 ± 0.62 nm, with polydispersity index, zeta potential, and entrapment efficiency (EE%) values of 0.326 ± 0.005, -22.08 ± 1.2 mV, and 98.93 ± 1.18%, respectively. According to high-resolution transmission electron microscopy (HRTEM) analysis, the droplets in the optimised formulation were < 60 nm in size. The selected SNEDDS released nearly 99% of the LPV within 30 min, which was significantly (p < 0.05) higher than the LPV-suspension in methylcellulose (0.5% w/v). It indicates the potential use of SNEDDS to enhance the solubility of LPV, which eventually could help improve the oral bioavailability of LPV. The Caco-2 cellular uptake study showed a significantly (p < 0.05) higher LPV uptake from the SNEEDS (LPV-SNEDDS-L-14) than the free LPV (LPV-suspension). The LPV-SNEDDS could be a potential carrier for LPV oral delivery.

Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal.

Antiretroviral drugs have dramatically improved the prognosis of HIV-infected patients, with strikingly reduced morbidity and mortality. However, long-term use can be associated with signs of premature aging. Highly active antiretroviral therapy generally comprises two nucleoside reverse transcriptase inhibitors (NRTIs), with one of three additional antiretroviral drug classes, including protease inhibitors (PIs). One commonality between mitochondrial dysfunction (induced by NRTIs) and defects in lamin A (induced by PIs) is they can cause or accelerate cellular senescence, a state of essentially irreversible growth arrest, and the secretion of many bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP). We hypothesized that senescent cells increase following treatment with certain HIV therapies. We compared the effects of two distinct HIV PIs: ritonavir-boosted atazanavir (ATV/r) and ritonavir-boosted darunavir (DRN/r), used in combination treatments for HIV infection. Upon ATV/r, but not DRN/r, treatment, cells arrested growth, displayed multiple features of senescence, and expressed significantly upregulated levels of many SASP factors. Furthermore, mice receiving sustained ATV/r treatment showed an increase in senescent cells and age-related decline in physiological function. However, removing treatment reversed the features of senescence observed in vivo and cell culture. Given how these features disappeared with drug removal, certain features of senescence may not be prognostic as defined by an irreversible growth arrest. Importantly, for patients that are treated or have been treated with ATV/r, our data suggest that switching to another PI that does not promote premature aging conditions (DRN/r) may improve the associated age-related complications.

Formulation and Evaluation of Solid-Self Nano Emulsifying Drug Delivery System of Darunavir

The main aim of this research article is to Formulate and Evaluate the S-SNEDDS of Darunavir. Darunavir is an anti-retroviral protease inhibitor which is in use from long time, but it has poor bioavailability because of poor aqueous solubility and extensive first pass metabolism, when used in the form of conventional dosage form. As it is a BCS Class II drug, which shows low solubility and high permeability. The S-SNEDDS of Darunavir was prepared to improve its oral bioavailability and its release rate was evaluated by in vitro release. The solubility of Darunavir in various oils was to decide and identify the oil phase of formulations. Different oils, surfactants and co-surfactants were screened for their ability to emulsify the selected oil. The pseudo ternary phase diagram was used to know the self -emulsification region of formulation. The optimized S-SNEDDS formulation contain Darunavir (150mg), Caproyl®90(50mg), Labrasol® and Transcutol® mix (45 mg). The data of the FTIR confirms that there is no interaction observed and the drug and excipients was compatible with each other. The developed SNEDDS formulations were examined for nano emulsifying capabilities, and the resulting nano emulsions were investigated for self-emulsification efficiency, dispersibility and in-vitro dissolution. Centrifugation tests, particle size distribution, heating cooling cycle, zeta potential, and freeze thaw cycling were performed on the optimised formulations to establish the stability of the produced SNEDDS formulation. Further produced S-SNEDDS micromeritics studies were done. The formulation was shown to significantly improve drug release, with total drug release occurring within 60 minutes. Darunavir self-emulsifying formulation was thus effectively produced.

Lopinavir-ritonavir for SARS-CoV-2 infection: a systematic review

Abstract Background SARS-CoV-2 is a new virus that first emerged in Wuhan, China in December 2019. The virus quickly spread throughout the countries, transforming the initial outbreak into a global pandemic. Lopinavir-ritonavir is an antiretroviral protease inhibitor combination drug that was proposed for the treatment of COVID-19 in the early phases of the pandemic. We conducted a systematic literature search on clinical trials assessing the efficacy and safety of lopinavir-ritonavir in patients hospitalized for COVID-19. 10 studies satisfying the inclusion criteria were analyzed and discussed in the current review. Four studies were randomized controlled trials, while the remaining had an observational design. The reported results are mixed, with some of the studies demonstrating the benefits of the combination drug, while others show little or no effect. These contradictory reports may be explained by the differences in study design, study population, the onset of treatment, and severity of disease, rendering this topic a subject for further debate.

HIV Drug Resistance Mutations

ART resistance, according to WHO, is the presence of one or more mutations in HIV that reduces the ability of certain drugs or drug groups to inhibit viral replication. According to the 2019 HIV Drug Resistance Report issued by the WHO, the prevalence of Antiretroviral Therapy (ART) drug resistance is 3%-29%. The prevalence of HIV drug resistance varies by country. In developed countries, the prevalence ranges from 6.6% to 11%. There are two types of resistance to ART: primary and secondary resistance. Primary resistance reflects the acquisition of drug-resistant strains in individuals who have recently been infected and have not received therapy. Secondary resistance occurs after treatment with ART. Resistance to antiretroviral therapy, mainly NRTIs, NNRTIs, and protease inhibitors, is caused by continuous inhibition of the HIV reverse transcriptase enzyme. World Health Organization (WHO) has recommended two NRTIs plus Lopinavir or Atazanavir as a second-line regimen for individuals who have failed treatment with efavirenz or dolutegravir; two NRTIs plus Darunavir and Lopinavir plus Raltegravir are recommended as an alternative due to cost constraints and the fact that Darunavir is unstable in moderately hot conditions.

Structure-based screening of natural product libraries in search of potential antiviral drug-leads as first-line treatment to COVID-19 infection

The study focuses on identifying and screening natural products (NPs) based on their structural similarities with chemical drugs followed by their possible use in first-line treatment to COVID-19 infection. In the present study, the in-house natural product libraries, consisting of 26,311 structures, were screened against potential targets of SARS-CoV-2 based on their structural similarities with the prescribed chemical drugs. The comparison was based on molecular properties, 2 and 3-dimensional structural similarities, activity cliffs, and core fragments of NPs with chemical drugs. The screened NPs were evaluated for their therapeutic effects based on their predicted in-silico pharmacokinetic and pharmacodynamics properties, binding interactions with the appropriate targets, and structural stability of the bound complex using molecular dynamics simulations. The study yielded NPs with significant structural similarities to synthetic drugs currently used to treat COVID-19 infections. The study proposes the probable biological action of the selected NPs as Anti-retroviral protease inhibitors, RNA-dependent RNA polymerase inhibitors, and viral entry inhibitors.

Potential Associations of Mutations within the HIV-1 Env and Gag Genes Conferring Protease Inhibitor (PI) Drug Resistance

An increasing number of patients in Africa are experiencing virological failure on a second-line antiretroviral protease inhibitor (PI)-containing regimen, even without resistance-associated mutations in the protease region, suggesting a potential role of other genes in PI resistance. Here, we investigated the prevalence of mutations associated with Lopinavir/Ritonavir (LPV/r) failure in the Envelope gene and the possible coevolution with mutations within the Gag-protease (gag-PR) region. Env and Gag-PR sequences generated from 24 HIV-1 subtype C infected patients failing an LPV/r inclusive treatment regimen and 344 subtype C drug-naïve isolates downloaded from the Los Alamos Database were analyzed. Fisher’s exact test was used to determine the differences in mutation frequency. Bayesian network probability was applied to determine the relationship between mutations occurring within the env and gag-PR regions and LPV/r treatment. Thirty-five mutations in the env region had significantly higher frequencies in LPV/r-treated patients. A combination of Env and Gag-PR mutations was associated with a potential pathway to LPV/r resistance. While Env mutations were not directly associated with LPV/r resistance, they may exert pressure through the Gag and minor PR mutation pathways. Further investigations using site-directed mutagenesis are needed to determine the impact of Env mutations alone and in combination with Gag-PR mutations on viral fitness and LPV/r efficacy.

Effect of HIV aspartyl protease inhibitors on experimental infection with a cystogenic Me49 strain of Toxoplasma gondii

ABSTRACT Toxoplasmosis is a zoonotic disease of major significant perspectives in public health and veterinary medicine. So far, the available drugs control only the active infection, once the parasite encysts in the tissues, they lose their efficacy. Cytokines; IFN-γ and IL-10, play a critical role in the modulation of toxoplasmic encephalitis and neuro-inflammation in chronic toxoplasmosis. Antiretroviral protease inhibitors applied in the treatment of acquired immunodeficiency syndrome, revealed activity against multiple parasites. Aluvia (lopinavir/ritonavir) (L/R); an aspartyl protease inhibitor, had efficiently treated T. gondii RH strain infection. We investigated the potential activity of L/R against experimental T. gondii infection with a cystogenic Me49 strain in mice, considering the role of IFN-γ and IL-10 in the neuropathology versus pyrimethamine-sulfadiazine combination therapy. Three aluvia regimens were applied; starting on the day of infection (acute phase), 2-week PI (early chronic phase) and eight weeks PI (late chronic phase). L/R reduced the brain-tissue cyst burden significantly in all treatment regimens. It impaired the parasite infectivity markedly in the late chronic phase. Ultrastructural changes were detected in Toxoplasma cyst membrane and wall, bradyzoite membrane and nuclear envelope. The signs of bradyzoite paraptosis and cytoplasmic lipid droplets were observed. L/R had significantly reduced the brain-homogenate levels of IFN-γ and IL-10 in its three regimens however, they could not reach the normal level in chronic phases. Cerebral hypercellularity, perivascular inflammatory response, lymphoplasmacytic infiltrates and glial cellular reaction were ameliorated by L/R treatment. Herein, L/R was proved to possess promising preventive and therapeutic perspectives in chronic cerebral toxoplasmosis.

Abstract 1164: Human endogenous retrovirus type K promotes proliferation of Merlin negative schwannoma and meningioma which can be inhibited by anti-retroviral and anti-TEAD drugs

Abstract Deficiency of the tumor suppressor Merlin causes the development of schwannoma, meningioma and ependymoma tumors. These can occur spontaneously or in the hereditary disease Neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Currently available treatments are surgery or radiosurgery which are only partially effective, with tumors frequently reoccurring and in case of meningioma often as a higher grade. There is an urgent need for effective drug treatments.In this study, we investigated the role of Human Endogenous Retrovirus Type K (HERV-K) and its targetability in Merlin negative schwannoma and meningioma tumors by using tissues and primary cells isolated form patients employing immunohistochemistry, immunocytochemistry, western blotting and proliferation assays. We demonstrate that HERV-K proteins are overexpressed in Merlin negative schwannoma and all meningioma grades. Furthermore, we implicate CRL4DCAF1 and YAPT/EAD Hippo pathway in this overexpression and suggest that exosome transport of the HERV-K Envelope (Env) protein might contribute to schwannoma development. We also show that: (i) Ectopic overexpression of HERV-K Env in normal Schwann cells increased proliferation and upregulated the transcription factor c-Jun. Env overexpression also increased activity of the extracellular signal-regulated kinase 1/2 (pERK1/2), a known mitogenic pathway in schwannoma. (ii) An anti-Env monoclonal antibody decreased pERK1/2 and reduced proliferation of schwannoma cells. iii) FDA-approved retroviral protease inhibitors Ritonavir, Atazanavir and Lopinavir decreased pERK1/2 and cyclin D1 and reduced proliferation of schwannoma and grade I meningioma cells. We provide evidence for HERV-K Env contributing to the development of NF2-associated schwannomas and meningiomas. Considering the urgent need of drugs to treat NF2, we suggest the trialling of antiretroviral protease inhibitors, and consideration of anti-HERV-K Env immunotherapy, as well as TEAD-specific inhibitors in these patients. The above treatments would also be potentially beneficial for patients with other tumors caused by Merlin deficiency. Citation Format: Sylwia Ammoun, Emmanuel A. Maze, Bora Agit, Robert Belshaw, C Oliver Hanemann. Human endogenous retrovirus type K promotes proliferation of Merlin negative schwannoma and meningioma which can be inhibited by anti-retroviral and anti-TEAD drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1164.

Anti-Retroviral Protease Inhibitors Regulate Human Papillomavirus 16 Infection of Primary Oral and Cervical Epithelium.

Simple SummaryIn 2016, globally, 36.7 million people were living with Human Immunodeficiency Virus (HIV), of which 53% had access to anti-retroviral therapy (ART) (UNAIDS 2017 Global HIV Statistics). The risk of Human Papillomavirus (HPV) associated oropharyngeal, cervical and anal cancers are higher among patients infected with HIV in the era of ART. Generally, HPV infections are self-limiting, however, persistent HPV infection is a major risk to carcinogenic progression. Long intervals between initial infection and cancer development imply cofactors are involved. Co-factors that increase infectivity, viral load, and persistence increase risk of cancer. We propose that the ART Protease Inhibitors (PI) class of drugs are novel co-factors that regulate HPV infection in HIV-infected patients. We developed a model system of organotypic epithelium to study impact of PI treatment on HPV16 infection. Our model could be used to study mechanisms of HPV infection in context of ART, and for developing drugs that minimize HPV infections.Epidemiology studies suggest that Human Immunodeficiency Virus (HIV)-infected patients on highly active anti-retroviral therapy (HAART) may be at increased risk of acquiring opportunistic Human Papillomavirus (HPV) infections and developing oral and cervical cancers. Effective HAART usage has improved survival but increased the risk for HPV-associated cancers. In this manuscript, we report that Protease Inhibitors (PI) treatment of three-dimensional tissues derived from primary human gingiva and cervical epithelial cells compromised cell-cell junctions within stratified epithelium and enhanced paracellular permeability of HPV16 to the basal layer for infection, culminating in de novo biosynthesis of progeny HPV16 as determined using 5-Bromo-2′-deoxyuridine (BrdU) labeling of newly synthesized genomes. We propose that HAART/PI represent a novel class of co-factors that modulate HPV infection of the target epithelium. Our in vitro tissue culture model is an important tool to study the mechanistic role of anti-retroviral drugs in promoting HPV infections in HAART-naïve primary epithelium. Changes in subsequent viral load could promote new infections, create HPV reservoirs that increase virus persistence, and increase the risk of oral and cervical cancer development in HIV-positive patients undergoing long-term HAART treatment.

Dynamics of fractional order HIV infection model with antibody and cytotoxic T-lymphocyte immune responses

This article concerns with the infection dynamics of fractionally extended HIV infection model incorporating antibody and cytotoxic T-Lymphocyte (CTL) immune responses. We study the role of antiretroviral therapy drugs, namely, reverse transcriptase and protease inhibitors in suppressing the HIV infection. The dynamical characteristics of the system are first discussed qualitatively through linear stability of stationary states and stable regions of the infectious and infection free steady states are figured out. The obtained results are compared with the results of integer order to understand the role of fractional order derivatives in HIV infection model. Besides the qualitative analysis on the system, we also look for the solution of the fractional system through numerical simulation.

Планирование и оценка исследований биоэквивалентности препаратов лопинавира/ритонавира

Рассмотрены вопросы планирования исследований биоэквивалентности препаратов лопинавира/ритонавира (LPV/RTV). LPV — противовирусное (ВИЧ) средство, ингибитор протеазы ВИЧ, который разрабатывался в фиксированной комбинации с RTV. Согласно действующему в РФ законодательству, при регистрации воспроизведенных лекарственных препаратов необходимо представление результатов исследований биоэквивалентности с референтным препаратом. Проведен анализ протоколов и отчетов исследований биоэквивалентности препаратов LPV/RTV в таблетированной лекарственной форме, поступивших на экспертизу в ФГБУ «НЦЭСМП» Минздрава России. Выявлены незначительные различия в дизайне исследований, включающие количество принимаемых таблеток и длительность отбора проб. Более существенные отличия наблюдались в количестве добровольцев, включенных в исследование, расчет которого основывается на значении коэффициента внутрииндивидуальной вариабельности LPV/RTV. Проведен поиск данных о вариабельности LPV/RTV в сети Интернет, некоторые результаты которого указывают на высокую вариабельность (&gt; 30 %) LPV/RTV. На основании проведенного анализа сформулированы рекомендации по планированию исследований биоэквивалентности препаратов LPV/RTV.

Synthesis and Characterization of Long-Acting Darunavir Prodrugs.

Antiretroviral therapy (ART) has improved the quality of life in patients infected with HIV-1. However, complete viral suppression within anatomical compartments remains unattainable. This is complicated by adverse side effects and poor adherence to lifelong therapy leading to the emergence of viral drug resistance. Thus, there is an immediate need for cellular and tissue-targeted long-acting (LA) ART formulations. Herein, we describe two LA prodrug formulations of darunavir (DRV), a potent antiretroviral protease inhibitor. Two classes of DRV prodrugs, M1DRV and M2DRV, were synthesized as lipophilic and hydrophobic prodrugs and stabilized into aqueous suspensions designated NM1DRV and NM2DRV. The formulations demonstrated enhanced intracellular prodrug levels with sustained drug retention and antiretroviral activities for 15 and 30 days compared to native DRV formulation in human monocyte-derived macrophages. Pharmacokinetics tests of NM1DRV and NM2DRV administered to mice demonstrated sustained drug levels in blood and tissues for 30 days. These data, taken together, support the idea that LA DRV with sustained antiretroviral responses through prodrug nanoformulations is achievable.

Factors associated with erectile dysfunction among men living with HIV: a systematic review

ABSTRACTErectile dysfunction (ED) is more prevalent among men with HIV than HIV negative men. This study systematically reviewed quantitative studies published since 1997 which sampled men with HIV to examine factors associated with ED. Searches on PsycINFO, Medline, Scopus, Embase and Cinahl databases produced 5552 records, and 14 studies met inclusion criteria. Two researchers independently extracted data and assessed the quality studies using standardized criteria. Age and depression were found to be significantly associated with ED. Importantly, factors unique to HIV emerged as consistently significant across studies, including time on antiretroviral medication and protease inhibitor medication use. However, these relate to organic cause factors associated with ED only. Only four studies examined social factors with inconsistent findings. There was a paucity of research related to psychosocial factors associated with ED. This systematic review used a broad search strategy employed across multiple data-bases, however, it is limited by the over-representation of treatment centre based studies conducted in high-income nations. Future research should examine psychosocial factors, such as undue fear of transmission of HIV or fear of rejection by a sexual partner and develop a psychosocial model of sexual difficulties with HIV, from which casual hypotheses can be derived and tested.

Indinavir-Loaded Nanostructured Lipid Carriers to Brain Drug Delivery: Optimization, Characterization and Neuropharmacokinetic Evaluation.

As an anti-retroviral Protease Inhibitor (PI), Indinavir (IDV) is part of the regimen known as Highly Active Anti-Retroviral Therapy (HAART) widely used for Human Immunodeficiency Virus (HIV) infection. The drug efficiency in treatment of the brain manifestations of HIV is, however, limited which is mainly due to the efflux by P-glycoprotein (P-gp) expressed at the Blood-Brain Barrier (BBB). To overcome the BBB obstacle, NLCs were used in this study as carriers for IDV, which were optimized through two steps: a "one-factor-at-a-time" screening followed by a systematic multiobjective optimization. Spherical smooth-surfaced Nanoparticles (NPs), average particle size of 161.02±4.8 nm, Poly-Dispersity Index (PDI) of 0.293±0.07, zeta potential of -40.62±2.21 mV, entrapment efficiency of 93±1.58%, and loading capacity of 9.15±0.15% were obtained after optimization which were, collectively, appropriate in terms of the objective of this study. The surface of the optimized NPs was, then, modified with human Transferrin (TR) to improve the drug delivery. The particle size, zeta potential, and PDI of the TR-modified NLCs were 185.29±6.7nm, -28.68±3.37 mV, and 0.247±0.06, respectively. The in vitro release of IDV molecules from the NPs was best fitted to the Weibull model indicating hybrid diffusion/erosion behavior. As the major in vivo findings, compared to the free drug, the NLCs and TR-NLCs displayed significantly higher and augmented concentrations in the brain. In this case, NLC and TR-NLC were 6.5- and 32.75-fold in their values of the brain uptake clearance compared to free drug.

Neuropharmacokinetic evaluation of lactoferrin-treated indinavir-loaded nanoemulsions: remarkable brain delivery enhancement

Objective: Indinavir (IDV), an antiretroviral protease inhibitor used in treatment of HIV infection, has limited entry into brain due to efflux by the P-glycoprotein presented in blood–brain barrier. The aim of present study was to develop lactoferrin-treated nanoemulsion containing indinavir (Lf-IDV-NEs) for delivery to brain. Methods: Indinavir-loaded nanoemulsions (IDV-NEs) were prepared by high-speed homogenization method, and then lactoferrin was coupled to IDV-NEs by water soluble EDC method. Results: The hydrodynamic diameters, polydispersity index, and zeta potential of IDV-NEs were 112 ± 3.5 nm, 0.20 ± 0.02, and −33.2 ± 2.6 mV, respectively. From in vivo studies in animal model of rats, the AUC0–4 h of brain concentration–time profile of IDV-NEs and Lf-IDV-NEs were 1.6 and 4.1 times higher than free drug, respectively. The brain uptake clearance of IDV-NEs and Lf-IDV-NEs were, interestingly, 393- and 420-times higher than the free drug. Conclusions: It can be concluded that applying both lactoferrin-treated and non-treated nanoemulsions clearly leads to significant brain penetration enhancement of indinavir, an effect which is more pronounced in the case of Lf-IDV-NEs with the higher drug residence time in brain.

Identification of Mechanism and Pathway of the Interaction between the African Traditional Medicine, Sutherlandia Frutescens, and the Antiretroviral Protease Inhibitor, Atazanavir, in Human Subjects Using Population Pharmacokinetic (PK) Analysis.

Although the use of the indigenous Southern African plant, Sutherlandia frutescens (SF) for the treatment of HIV/AIDS has previously been described, the risk which it may pose to the safety and efficacy of ARVs and the potential mechanisms which underlie such effects may have clinical significance and relevance. The protease inhibitor (PI), atazanavir (ATV) is a substrate of the efflux transporter, P-gp which modulates absorption in the small intestine, as well as CYP3A4 and CYP3A5enzymes which facilitate metabolism in the small intestine and liver. The objective of this study was to investigate the effect of SF on the pharmacokinetics (PK) of atazanavir (ATV) and to use a population PK analysis to fit and explain plasma concentration vs. time profiles of ATV generated in a previously conducted study in healthy male subjects in order to understand and postulate on the potential mechanism(s) of the drug-drug interaction. The population PK Compartmental Analysis of ATV before and after a two-week regimen of Phyto Nova Sutherlandia SU1 tablets which contain SF plant material indicated that a two compartment model with a dual absorption mechanism best explained the data. The dual absorption mechanism is hypothesized to reflect "passive" (first-order, Ka parameter) and "active" (zero-order, K0 parameter) absorption processes. The model suggested that the mechanism by which SF reduced the overall bioavailability of ATV may be modulated via the inhibition of the "active" absorption process. This study has highlighted the utility of population PK analyses in postulating probable mechanism(s) whereby an ATM or a herbal medicine interacts with an allopathic drug.

Outcome effects of antiretroviral drug combinations in HIV-positive patients with chemotherapy for lymphoma: a retrospective analysis

Background The combination of combined active antiretroviral therapy (cART) with chemotherapy in the treatment of lymphoma in human immunodeficiency virus (HIV)-positive patients has improved the overall survival of these patients. However, drug–drug interactions between antineoplastic agents and the antiretroviral agents non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) can occur by influencing the activity of the CYP3A4 enzyme. So far, little is known about the clinical relevance of this interaction: the effect on the efficacy and toxicity of the chemotherapy. Also, there is no general consensus which cART is preferable in combination with antineoplastic drugs. Objective To compare PI-based with NNRTI-based cART on the efficacy and toxicity of chemotherapy in lymphoma patients. Setting The Onze Lieve Vrouwe Gasthuis, located in Amsterdam, The Netherlands. Method A retrospective observational cohort study including all patients with HIV and lymphoma over a 10-year period. Clinical outcome (response to chemotherapy and survival) and toxicity of chemotherapy (renal, hepatic and bone marrow toxicity as well as dose reduction, treatment delay and discontinuation) was compared in patients with PI based and NNRTI-based cART. Main outcome measure: Response to chemotherapy and survival. Results Patients using PI-based cART (n = 22) had a significantly lower 1 year survival compared to NNRTI-based cART (n = 21). No significant differences were observed in reaching complete remission after chemotherapy. No overall significant differences in toxicity and discontinuation of the chemotherapy were observed. However, there was a trend towards more severe bone-marrow toxicity in patients with PI-based cART. In addition, patients with PI-based cART received earlier dose-reduction and treatment delay, indicating increased toxicity in PI-treated patients. Conclusion This retrospective study shows that PI-based cART is inferior in combination with chemotherapy to NNRTI-based cART: a lower 1 year survival is observed and dose-reduction and treatment delay occur earlier, possibly based on an earlier onset of toxicity.