- Desolvation behavior of indinavir sulfate ethanol and follow-up by terahertz spectroscopy. [Journal Article]
- IJInt J Pharm 2019 Jun 17
- Active pharmaceutical ingredients are composed of single-component or multicomponent crystals. Multicomponent crystals include salts, co-crystals, and solvates. Indinavir sulfate is the ethanol solva…
Active pharmaceutical ingredients are composed of single-component or multicomponent crystals. Multicomponent crystals include salts, co-crystals, and solvates. Indinavir sulfate is the ethanol solvate form of indinavir that is known to deliquesce through moisture absorption. However, the detailed behavior of solvent molecules in the crystal has not been investigated. In this study, we studied the desolvation mechanism of indinavir sulfate ethanol and investigated the behavior of solvent molecules in the solid from. Indinavir sulfate ethanol contained 1.7 molecules of ethanol, 0.7 of which desolvated at room temperature. They were originally two ethanol solvent molecules; one molecule of ethanol desolvated at room temperature, and the conformation of the remaining ethanol and t-butyl groups changed in conjunction with the removal of one ethanol molecule. Desolvation could hardly be detected by powder X-ray diffraction; however, it was detected using terahertz spectroscopy. Terahertz measurement of desolvation showed a high correlation with thermogravimetry data, suggesting that desolvation could be observed non-destructively using terahertz spectroscopy. We concluded that indinavir sulfate 1 ethanol deliquesced at 60% relative humidity, and it turned into an amorphous solid after drying.
- Core-Shell Palladium Telluride Quantum Dot-Hemethiolate Cytochrome Based Biosensor for Detecting Indinavir Drug. [Journal Article]
- JNJ Nanosci Nanotechnol 2019 Dec 01; 19(12):7974-7981
- Indinavir is a first-generation HIV protease inhibitor anti-retroviral (ARV) drug. Due to interindividual differences in the rate of indinavir metabolism, clinicians and pharmacologists have expresse…
Indinavir is a first-generation HIV protease inhibitor anti-retroviral (ARV) drug. Due to interindividual differences in the rate of indinavir metabolism, clinicians and pharmacologists have expressed urgent need for sensor devices that will enable real time determination of appropriate dosage. In this study, an indinavir biosensor was developed by the functionalization of a cysteamine-modified gold (Cyst|Au) electrode with biocompatible core-shell 3-mercaptopropionic acid (3-MPA)-capped palladium telluride quantum dot (PdTeQD) and the heme-thiolate cytochrome P450-3A4 (CYP3A4) enzyme. The PdTeQD was capped with 3-mercaptopropionic acid (3-MPA) to improve its reactivity, biocompatibility and thermal stability. Small angle X-ray scattering (SAXS) studies revealed that the 3-MPA-PdTeQD particles formed core-shells with diameters of 4.7 nm. Fourier transformed infrared spectroscopy (FTIR) experiments confirmed the formation of 3-MPA-PdTeQD by the presence of specific COOH and CH₂ FTIR signature bands. Ultraviolet-visible (UV-Vis) spectrophotometric analysis of the quantum dot, exhibited a broad characteristic band at ~320 nm, corresponding to a band gap energy (Eg) value of 3.87 eV, indicating that the QD is a semiconducting material. Cyclic voltammetry (CV) responses of the biosensor (i.e., CYP3A4|3-MPA-PdTeQD|Cyst|Au) indicated that 0.26 V was the suitable potential for measuring indinavir metabolism. The biosensor has a sensitivity, dynamic linear range (DLR) and limit of detection (LOD) values of 0.0218 μA/nM, 0.0004-0.01 nM (i.e., 3×10-7 -7×10-6 mg L-1) and 0.023×10-7 mg L-1, respectively, for indinavir. The LOD value was lower than the maximum plasma concentration (Cmax) value (0.13-8.6 mg L-1) of indinavir which is normally measure 8 h after intake. The low DLR value makes the biosensor suitable for application at point-of-care, where indinavir concentration is expected to be in ng L-1 level in physiological samples within a few minutes of the drug administration.
- Oral delivery of indinavir using mPEG-PCL nanoparticles: preparation, optimization, cellular uptake, transport and pharmacokinetic evaluation. [Journal Article]
- ACArtif Cells Nanomed Biotechnol 2019; 47(1):2123-2133
- CONCLUSIONS: The results of this study are promising for the use of biodegradable polymeric nanoparticles to improve oral drug delivery.
- The mechanism for differential effect of nelfinavir and indinavir on collagen metabolism in human skin fibroblasts. [Journal Article]
- EDExp Dermatol 2019; 28(7):845-853
- The mechanism for differential effects of human immune deficiency virus protease inhibitors (HIVPIs), nelfinavir (NEL) and indinavir (IND) on collagen metabolism disturbances was studied in human ski…
The mechanism for differential effects of human immune deficiency virus protease inhibitors (HIVPIs), nelfinavir (NEL) and indinavir (IND) on collagen metabolism disturbances was studied in human skin fibroblasts. It has been considered that HIVPIs-dependent deregulation of collagen biosynthesis involves prolidase (an enzyme providing proline for collagen biosynthesis), glutamine (Gln) (a substrate for proline biosynthesis), nuclear factor-κB (NF-κB) (a transcription factor that inhibit expression of type I collagen genes), β1 integrin receptor and Akt signalling. It was found that NEL impaired collagen biosynthesis and the process was more pronounced in the presence of Gln, while IND stimulated collagen biosynthesis. NEL-dependent inhibition of collagen biosynthesis was accompanied by massive intracellular accumulation of type I collagen, while IND slightly induced this process. This effect of NEL was reversed by ascorbic acid but not N-acetylcysteine. The mechanism for the NEL-dependent defect in collagen metabolism was found at the level of prolidase activity, β1 integrin signalling and NF-κB. NEL inhibited expression of β1 integrin receptor, Akt and ERK1/2 and increased expression of p65 NF-κB. However, inhibitors of p65 NF-κB did not prevent NEL-dependent inhibition of collagen biosynthesis suggesting that this transcription factor is not involved in studied mechanism. Using PI3K inhibitor wortmannin that prevent phosphorylation of Akt revealed that NEL-dependent inhibition of Akt results in inhibition of collagen biosynthesis. The data suggest that differential effect of NEL and IND on collagen metabolism involves NEL-dependent down-regulation of Akt signalling and proline availability for collagen biosynthesis.
- Biorelevant dissolution testing of a weak base: Interlaboratory reproducibility and investigation of parameters controlling in vitro precipitation. [Journal Article]
- EJEur J Pharm Biopharm 2019; 140:141-148
- Following a previous study which aimed to determine the interlaboratory reproducibility of biorelevant dissolution testing in the USP 2 apparatus for commercial formulations of two weak acids (ibupro…
Following a previous study which aimed to determine the interlaboratory reproducibility of biorelevant dissolution testing in the USP 2 apparatus for commercial formulations of two weak acids (ibuprofen and zafirlukast), this study attempts to determine the interlaboratory reproducibility using a similar protocol for a commercially available formulation of a weak base, indinavir. Fourteen partners including twelve industrial and two academic partners participated in this study. To ensure uniformity, all partners were provided with a standardized protocol to perform (i) a single medium dissolution test in fasted state simulated gastric and intestinal fluids (FaSSGF and FaSSIF, respectively) and (ii) a two-stage dissolution experiment simulating gastrointestinal transfer. Optionally, partners could run a single-stage dissolution test in fed state simulated intestinal fluid (FeSSIF). For each dissolution test, one Crixivan® capsule (containing 400 mg indinavir as its sulfate salt) was added as dose of interest. For the single medium dissolution test in FaSSIF, all partners observed rapid release of indinavir resulting in supersaturated concentrations, followed by precipitation to equilibrium solubility. The degree and period of supersaturation varied among the participating laboratories. Average dissolution profiles in FeSSIF appeared to be highly reproducible with dissolved concentrations remaining lower than the thermodynamic solubility of indinavir in FeSSIF. For the two-stage dissolution test, most partners observed supersaturated concentrations in the intestinal compartment; two partners observed no supersaturation due to immediate precipitation. Given the fact that a high interlaboratory but low intralaboratory variability was observed when supersaturation/precipitation occurred, an undefined factor was hypothesized as a potential cause of the variability in precipitation. Hence, the impact of several experimental factors on the supersaturation and precipitation behavior of indinavir was investigated in a next step. The investigation indicated that variability is likely attributable to a combination of factors, especially, the time elapsed between sampling and dilution of the sample with the mobile phase. Therefore, when designing a test in which supersaturation and precipitation is anticipated, stringent control of the test methodology, especially regarding sampling and dilution, is needed.
- Indinavir Increases Midazolam N-Glucuronidation in Humans: Identification of an Alternate CYP3A Inhibitor Using an In Vitro to In Vivo Approach. [Journal Article]
- DMDrug Metab Dispos 2019; 47(7):724-731
- Midazolam is a widely used index substrate for assessing effects of xenobiotics on CYP3A activity. A previous study involving human hepatocytes showed the primary route of midazolam metabolism, 1'-hy…
Midazolam is a widely used index substrate for assessing effects of xenobiotics on CYP3A activity. A previous study involving human hepatocytes showed the primary route of midazolam metabolism, 1'-hydroxylation, shifted to N-glucuronidation in the presence of the CYP3A inhibitor ketoconazole, which may lead to an overprediction of the magnitude of a xenobiotic-midazolam interaction. Because ketoconazole is no longer recommended as a clinical CYP3A inhibitor, indinavir was selected as an alternate CYP3A inhibitor to evaluate the contribution of the N-glucuronidation pathway to midazolam metabolism. The effects of indinavir on midazolam 1'-hydroxylation and N-glucuronidation were first characterized in human-derived in vitro systems. Compared with vehicle, indinavir (10 μM) inhibited midazolam 1'-hydroxylation by recombinant CYP3A4, human liver microsomes, and high-CYP3A activity cryopreserved human hepatocytes by ≥70%; the IC50 obtained with hepatocytes (2.7 μM) was within reported human unbound indinavir Cmax (≤5 μM). Midazolam N-glucuronidation in hepatocytes increased in the presence of indinavir in both a concentration-dependent (1-33 μM) and time-dependent (0-4 hours) manner (by up to 2.5-fold), prompting assessment in human volunteers (n = 8). As predicted by these in vitro data, indinavir was a strong inhibitor of the 1'-hydroxylation pathway, decreasing the 1'-hydroxymidazolam/midazolam area under the plasma concentration versus time curve (AUC)0-12h ratio by 80%. Although not statistically significant, the midazolam N-glucuronide/midazolam AUC0-12h ratio increased by 40%, suggesting a shift to the N-glucuronidation pathway. The amount of midazolam N-glucuronide recovered in urine increased 4-fold but remained <10% of the oral midazolam dose (2.5 mg). A powered clinical study would clarify whether N-glucuronidation should be considered when assessing the magnitude of a xenobiotic-midazolam interaction.
- PEDF increases GLUT4-mediated glucose uptake in rat ischemic myocardium via PI3K/AKT pathway in a PEDFR-dependent manner. [Journal Article]
- IJInt J Cardiol 2019 May 15; 283:136-143
- CONCLUSIONS: PEDF can increase glucose uptake in ischemic myocardium through a PEDFR-dependent mechanism, involving PI3K/AKT signaling and GLUT4 translocation.
- Indinavir-Loaded Nanostructured Lipid Carriers to Brain Drug Delivery: Optimization, Characterization and Neuropharmacokinetic Evaluation. [Journal Article]
- CDCurr Drug Deliv 2019; 16(4):341-354
- CONCLUSIONS: 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.
- Modern Computational Strategies for Designing Drugs to Curb Human Diseases: A Prospect. [Review]
- CTCurr Top Med Chem 2018; 18(31):2702-2719
- Drug discovery is an exhaustive and time-consuming process involving numerous stages like target identification, validation, lead optimization, preclinical trials, clinical trials and finally postmar…
Drug discovery is an exhaustive and time-consuming process involving numerous stages like target identification, validation, lead optimization, preclinical trials, clinical trials and finally postmarketing vigilance for drug safety. The application of computer-aided drug designing (CADD) is an indispensable approach for developing safe and effective drugs. Previous methods based on combinatorial chemistry (CC) and high throughput screening (HTS) consumed a lot of time as well as expenditure. CADD based approaches including pharmacophore modeling (PM), molecular docking (MD), inverse docking, chemical similarity (CS), quantitative structure-activity relationship (QSAR), virtual screening (VS) and molecular dynamics simulations have been quite productive in predicting the therapeutic outcome of candidate drugs/compounds besides saving precious time. CADD tools exploit structural and other information available regarding the target (enzyme/receptor) and the ligands to identify the compounds with the ability to treat diseases notably cancer, neurodegenerative disorders, malaria, Ebola, HIV-AIDS and many more. Computational approaches have led to the discovery of many drugs that have passed preclinical and clinical trials and become novel therapeutics in the treatment of a variety of diseases. Some notable examples of CADD derived novel drugs include dorzolamide, saquinavir, ritonavir, indinavir, captopril and tirofiban. CADD plays important role in predicting absorption, distribution, metabolism, excretion and toxicity (ADME/T) of candidate drugs. Overall, CADD represents an effective and much-needed strategy for designing therapeutically effective drugs to combat human diseases.
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- Leishmanicidal therapy targeted to parasite proteases. [Review]
- LSLife Sci 2019 Feb 15; 219:163-181
- Leishmaniasis is considered a serious public health problem and the current available therapy has several disadvantages, which makes the search for new therapeutic targets and alternative treatments …
Leishmaniasis is considered a serious public health problem and the current available therapy has several disadvantages, which makes the search for new therapeutic targets and alternative treatments extremely necessary. In this context, this review focuses on the importance of parasite proteases as target drugs against Leishmania parasites, as a chemotherapy approach. Initially, we discuss about the current scenario for the treatment of leishmaniasis, highlighting the main drugs used and the problems related to their use. Subsequently, we describe the inhibitors of major proteases of Leishmania already discovered, such as Compound s9 (aziridine-2,3-dicarboxylate), Compound 1c (benzophenone derivative), Au2Phen (gold complex), AubipyC (gold complex), MDL 28170 (dipeptidyl aldehyde), K11777, Hirudin, diazo-acetyl norleucine methyl ester, Nelfinavir, Saquinavir, Nelfinavir, Saquinavir, Indinavir, Saquinavir, GNF5343 (azabenzoxazole), GNF6702 (azabenzoxazole), Benzamidine and TPCK. Next, we discuss the importance of the protease gene to parasite survival and the aspects of the validation of proteases as target drugs, with emphasis on gene disruption. Then, we describe novel important strategies that can be used to support the research of new antiparasitic drugs, such as molecular modeling and nanotechnology, whose main targets are parasitic proteases. And finally, we discuss possible perspectives to improve drug development. Based on all findings, proteases could be considered potential targets against leishmaniasis.