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The Effect of Switching from Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide (TAF) on Liver Enzymes, Glucose, and Lipid Profile.
Squillace, N, Ricci, E, Menzaghi, B, De Socio, GV, Passerini, S, Martinelli, C, Mameli, MS, Maggi, P, Falasca, K, Cordier, L, et al
Drug design, development and therapy. 2020;:5515-5520
Abstract
OBJECTIVE We aimed to investigate the effect of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) on the hepatic safety and metabolic profile. METHODS Consecutive HIV patients, enrolled in the Surveillance Cohort Long-term Toxicity Antiretrovirals/Antivirals (SCOLTA) project, switching from TDF to TAF were included. Changes from baseline (T0) to 6-month follow-up (T1) were evaluated using paired t-test and signed rank test. RESULTS A total of 190 patients switched from TDF to TAF and had one 6-month follow-up visit. They were 80% male, 74.2% at CDC stage A-B, 93.7% with undetectable HIV-viral load. Mean age was 46.7±10.7 years, body mass index was 25.0±3.9 kg/m2, median CD4 cell count was 634 cell/µL (interquartile range [IQR]=439-900), aspartate aminotransferase (AST) was 23 (IQR=19-30) IU/L, and alanine aminotransferase (ALT) was 24 (IQR=17-34) IU/L. At T1, both AST (median=-1, IQR=-5-2 IU/L, P=0.004) and ALT (median=-2, IQR=-7-3 IU/L, P=0.0004) showed a significant decrease. Among 28 patients with ALT >40 at baseline, reduction was significant both clinically (-17, IQR=-32--1) and statistically (P=0.0003). Total cholesterol levels (TC) increased (+13.4±3.8 mg/dL, P=0.0006), as well as HDL-cholesterol (HDL-C) (+3.8±1.2 mg/dL, P=0.02), LDL Cholesterol (LDL-C) (+7.6±3.4, P=0.03) and glucose (+4.0±1.8 mg/dL, P=0.02). D:A:D: and Framingham risk score did not change at 6 months after switch. CONCLUSION A significant reduction of liver enzymes was observed after switching from TDF to TAF, especially in subjects with initial level of ALT >40 IU/L. Glucose, TC, HDL-C, and LDL-C increased, with no effect on cardiovascular risk scores.
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Long-Term Effects of Safinamide on Mood Fluctuations in Parkinson's Disease.
Cattaneo, C, Müller, T, Bonizzoni, E, Lazzeri, G, Kottakis, I, Keywood, C
Journal of Parkinson's disease. 2017;(4):629-634
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BACKGROUND Mood disorders are very frequent in Parkinson's Disease (PD), and their effective treatment is still a major unresolved issue: growing evidence suggests that glutamatergic system dysfunction is directly involved. Safinamide is a drug with an innovative mechanism of action, dopaminergic and non-dopaminergic, that includes the reversible inhibition of the monoamine oxidase-B (MAO-B) enzyme and the modulation of excessive glutamate release through the use- and state-dependent blockade of the sodium channels. OBJECTIVE To investigate the effects of safinamide on mood over two-year treatment in PD patients with motor fluctuations. METHODS This was a post-hoc analysis of the data from studies 016 and 018. The analysis focused on outcomes related to mood, namely: scores of the "Emotional well-being" domain of the Parkinson's Disease Questionnaire (PDQ-39), scores of the GRID Hamilton Rating Scale for Depression (GRID-HAMD) and the proportion of patients reporting depression as an adverse event over the entire treatment period. RESULTS Safinamide, compared to placebo, significantly improved the PDQ-39 "Emotional well-being" domain after6-months (p = 0.0067) and 2 years (p = 0.0006), as well as the GRID-HAMD (p = 0.0408 after 6 months and p = 0.0027 after 2 years). Significantly fewer patients in the safinamide group, compared to placebo, experienced depression as adverse event (p = 0.0444 after 6 months and p = 0.0057 after 2 years). CONCLUSION The favorable effect of safinamide on mood may be explained by the improvement in wearing off and by its modulation of glutamatergic hyperactivity and reversible MAO-B inhibition. Prospective studies are warranted to investigate this potential benefit.
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Effect of enzyme inhibition on perampanel pharmacokinetics: Why study design matters.
Gidal, BE, Maganti, R, Laurenza, A, Yang, H, Verbel, DA, Schuck, E, Ferry, J
Epilepsy research. 2017;:41-48
Abstract
OBJECTIVES Perampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12years and older. In vitro studies and Phase I trials indicate that perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t1/2) averaging approximately 105h. Understanding of pharmacokinetic (PK) interactions-enzyme inhibition or induction-and anticipating their occurrence are important for management of patients with epilepsy. Here we report PK results from a Phase I drug-drug interaction (DDI) study (Study 005) combining perampanel with the CYP3A inhibitor ketoconazole, as well as supplementary in silico predictions further exploring this interaction. METHODS A Phase I, randomized, open-label, two-period, two-treatment, two-way crossover study was conducted in 26 healthy adult male volunteers. Subjects were randomized to 1 of 2 treatment sequences. In one period, subjects received a single 1-mg fasting dose of perampanel (Day1); in the other period, subjects received ketoconazole 400mg once daily for 10days with a single 1-mg perampanel dose while fasting (Day3). Blood samples were drawn at multiple time points up to 288h after the perampanel dose. Pharmacokinetic parameters of perampanel were calculated by noncompartmental analysis, and safety was recorded. An integrated, physiologically based PK model built in Simcyp® provided additional insight into this interaction. Drug-drug interaction intensity was measured by the ratio of systemic exposure (area under plasma concentration-time curve [AUC]) of perampanel in the presence or absence of concomitant ketoconazole. RESULTS Single oral doses of 1mg perampanel and once-daily oral doses of ketoconazole 400mg were safe and well tolerated. Maximum perampanel plasma concentration (Cmax) and time to Cmax showed no apparent differences when perampanel was administered alone versus with ketoconazole. Ketoconazole co-administration resulted in an approximate 20% increase in perampanel AUC (P<0.001). This increase, although statistically significant, was a<2.0-fold AUC change and alone would suggest a modest effect of ketoconazole. To further explore these results, DDI simulations were performed to query the findings and test additional study conditions. Using the actual trial conditions of Study 005, the simulations also predicted an AUC ratio increase <2-fold, providing verification of the simulation assumptions and the modest effect of ketoconazole for 10days. Simulations further suggested that an interaction effect of ketoconazole on perampanel exposure (>2-fold) of potential clinical significance could be predicted when using larger doses of ketoconazole (e.g., 200mg every 6h) coadministered for a greater time period (e.g., 30days), with AUC ratio as high as 3.36. Additionally, simulations suggested that a significant interaction with co-administration of perampanel and an inhibitor more potent than ketoconazole (such as itraconazole) could not be ruled out. CONCLUSIONS Selecting an appropriate study design is critical to fully characterize the PK interaction for drugs such as perampanel that have a long t1/2. Although a negligible effect on perampanel PK was observed following co-administration of ketoconazole 400mg/day for 10days, this is likely due in part to the relatively brief co-administration period of ketoconazole and perampanel (<3 times the t1/2 of perampanel). While short-term administration of a CYP3A inhibitor may not significantly increase perampanel exposure, such increases may be expected following chronic and larger dosing or with a more potent inhibitor.
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2-Phenethyl Isothiocyanate, Glutathione S-transferase M1 and T1 Polymorphisms, and Detoxification of Volatile Organic Carcinogens and Toxicants in Tobacco Smoke.
Yuan, JM, Murphy, SE, Stepanov, I, Wang, R, Carmella, SG, Nelson, HH, Hatsukami, D, Hecht, SS
Cancer prevention research (Philadelphia, Pa.). 2016;(7):598-606
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Cigarette smoke contains relatively large quantities of volatile organic toxicants or carcinogens such as benzene, acrolein, and crotonaldehyde. Among their detoxification products are mercapturic acids formed from glutathione conjugation, catalyzed in part by glutathione S-transferases (GST). A randomized phase II clinical trial with a crossover design was conducted to evaluate the effect of 2-phenethyl isothiocyanate (PEITC), a natural product formed from gluconasturtiin in certain cruciferous vegetables, on the detoxification of benzene, acrolein, and crotonaldehyde in 82 cigarette smokers. Urinary mercapturic acids of benzene, acrolein, and crotonaldehyde at baseline and during treatment were quantified. Overall, oral PEITC supplementation increased the mercapturic acid formed from benzene by 24.6% (P = 0.002) and acrolein by 15.1% (P = 0.005), but had no effect on crotonaldehyde. A remarkably stronger effect was observed among subjects with the null genotype of both GSTM1 and GSTT1: in these individuals, PEITC increased the detoxification metabolite of benzene by 95.4% (P < 0.001), of acrolein by 32.7% (P = 0.034), and of crotonaldehyde by 29.8% (P = 0.006). In contrast, PEITC had no effect on these mercapturic acids in smokers possessing both genes. PEITC had no effect on the urinary oxidative stress biomarker 8-iso-prostaglandin F2α or the inflammation biomarker prostaglandin E2 metabolite. This trial demonstrates an important role of PEITC in detoxification of environmental carcinogens and toxicants which also occur in cigarette smoke. The selective effect of PEITC on detoxification in subjects lacking both GSTM1 and GSTT1 genes supports the epidemiologic findings of stronger protection by dietary isothiocyanates against the development of lung cancer in such individuals. Cancer Prev Res; 9(7); 598-606. ©2016 AACR.
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IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells.
Dong, S, Guinn, D, Dubovsky, JA, Zhong, Y, Lehman, A, Kutok, J, Woyach, JA, Byrd, JC, Johnson, AJ
Blood. 2014;(24):3583-6
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Chronic lymphocytic leukemia (CLL) displays constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of B-cell receptor (BCR) signaling. Previous studies have shown that an oral PI3K p110δ inhibitor idelalisib exhibits promising activity in CLL. Here, we demonstrate that a dual PI3K p110δ and p110γ inhibitor, IPI-145, antagonizes BCR crosslinking activated prosurvival signals in primary CLL cells. IPI-145 causes direct killing in primary CLL cells in a dose- and time-dependent fashion, but does not generate direct cytotoxicity to normal B cells. However, IPI-145 does reduce the viability of normal T and natural killer cells and decrease activated T-cell production of various inflammatory and antiapoptotic cytokines. Furthermore, IPI-145 overcomes the ibrutinib resistance resulting from treatment-induced BTK C481S mutation. Collectively, these studies provide rationale for ongoing clinical evaluation of IPI-145 as a targeted therapy for CLL and related B-cell lymphoproliferative disorders.
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Is (+)-[13C]-pantoprazole better than (±)-[13C]-pantoprazole for the breath test to evaluate CYP2C19 enzyme activity?
Thacker, DL, Modak, A, Flockhart, DA, Desta, Z
Journal of breath research. 2013;(1):016001
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Recently, we have shown that the (+)-[(13)C]-pantoprazole is more dependent on CYP2C19 metabolic status than (-)-[(13)C]-pantoprazole. In this study, we tested the hypothesis that (+)-[(13)C]-pantoprazole is a more sensitive and selective probe for evaluating CYP2C19 enzyme activity than the racemic mixture. (+)-[(13)C]-pantoprazole (95 mg) was administered orally in a sodium bicarbonate solution to healthy volunteers. Breath and plasma samples were collected before and up to 720 min after dosing. The (13)CO2 in exhaled breath samples was measured by infrared spectrometry. Ratios of (13)CO2/(12)CO2 after (+)-[(13)C]-pantoprazole relative to (13)CO2/(12)CO2 at baseline were expressed as delta over baseline (DOB). (+)-[(13)C]-pantoprazole concentrations were measured by HPLC. Genomic DNA extracted from whole blood was genotyped for CYP2C19*2, *3 and *17 using Taqman assays. Statistically significant differences in the area under the plasma concentration time curve (AUCplasma(0-∞) (p < 0.001) and oral clearance (<0.01) of (+)-[(13)C]-pantoprazole as well as in the breath test indices (delta over baseline, DOB30; and area under the DOB versus time curve, AUCDOB(0-120)) (p < 0.01) were observed among poor, intermediate and extensive metabolizer of CYP2C19. DOB30 and AUCDOB(0-120) adequately distinguished poor metabolizer from intermediate and extensive metabolizer of CYP2C19. Breath test indices significantly correlated with plasma elimination parameters of (+)-[(13)C]-pantoprazole (Pearson correlations: -0.68 to -0.73). Although relatively higher breath test indices were observed after administration of (+)-[(13)C]-pantoprazole (this study) than after (±)-[(13)C]-pantoprazole (previous study), the performance of the racemic and the enantiomer as marker of CYP2C19 activity remained similar. Our data confirm that the metabolism of (+)-[(13)C]-pantoprazole is highly dependent on CYP2C19 metabolic status, but the breath test derived from it is not superior to the racemic [(13)C]-pantoprazole in evaluating CYP2C19 activity in vivo. Thus, racemic [(13)C]-pantoprazole which is relatively easy to synthesize and more stable than (+)-[(13)C]-pantoprazole is adequate as a probe of this enzyme.
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Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers.
Pithavala, YK, Tong, W, Mount, J, Rahavendran, SV, Garrett, M, Hee, B, Selaru, P, Sarapa, N, Klamerus, KJ
Investigational new drugs. 2012;(1):273-81
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OBJECTIVE Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by cytochrome P450 (CYP) 3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. Co-administration with CYP inhibitors may increase systemic exposure to axitinib and alter its safety profile. This study evaluated changes in axitinib plasma pharmacokinetic parameters and assessed safety and tolerability in healthy subjects, following axitinib co-administration with the potent CYP3A inhibitor ketoconazole. METHODS In this randomized, single-blind, two-way crossover study, 32 healthy volunteers received placebo, followed by a single 5-mg oral dose of axitinib, administered either alone or on the fourth day of dosing with oral ketoconazole (400 mg/day for 7 days). RESULTS Axitinib exposure was significantly increased in the presence of ketoconazole, with a geometric mean ratio for area under the plasma concentration-time curve from time zero to infinity of 2.06 (90% confidence interval [CI]: 1.84-2.30) and a geometric mean ratio for maximum plasma concentration (C(max)) of 1.50 (90% CI: 1.33-1.70). For axitinib alone or with ketoconazole, C(max) occurred 1.5 and 2.0 h after dosing, respectively. Adverse events were predominantly mild; the most commonly reported treatment-related adverse events were headache and nausea. CONCLUSIONS Axitinib plasma exposures and peak concentrations were increased following concurrent administration of axitinib and ketoconazole in healthy volunteers. Axitinib alone and in combination with ketoconazole was well tolerated. These findings provide an upper exposure for expected axitinib plasma concentrations in the presence of potent metabolic inhibition.
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Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study.
Kunos, C, Radivoyevitch, T, Abdul-Karim, FW, Fanning, J, Abulafia, O, Bonebrake, AJ, Usha, L
Journal of translational medicine. 2012;:79
Abstract
BACKGROUND The potent ribonucleotide reductase (RNR) inhibitor 3-aminopyridine-2-carboxyaldehyde-thiosemicarbazone (3-AP) was tested as a chemosensitizer for restored cisplatin-mediated cytotoxicity in platinum-resistant ovarian cancer. METHODS Preclinical in vitro platinum-resistant ovarian cancer cell survival, RNR activity, and DNA damage assays were done after cisplatin or cisplatin plus 3-AP treatments. Six women with platinum-resistant ovarian cancer underwent four-day 3-AP (96 mg/m(2), day one to four) and cisplatin (25 mg/m(2), day two and three) infusions every 21 days until disease progression or adverse effects prohibited further therapy. Pre-therapy ovarian cancer tissues were analyzed by immunohistochemistry for RNR subunit expression as an indicator of cisplatin plus 3-AP treatment response. RESULTS 3-AP preceding cisplatin exposure in platinum-resistant ovarian cancer cells was not as effective as sequencing cisplatin plus 3-AP together in cell survival assays. Platinum-mediated DNA damage (i.e., γH2AX foci) resolved quickly after cisplatin-alone or 3-AP preceding cisplatin exposure, but persisted after a cisplatin plus 3-AP sequence. On trial, 25 four-day overlapping 3-AP and cisplatin cycles were administered to six women (median 4.2 cycles per patient). 3-AP-related methemoglobinemia (range seven to 10%) occurred in two (33%) of six women, halting trial accrual. CONCLUSIONS When sequenced cisplatin plus 3-AP, RNR inhibition restored platinum-sensitivity in platinum-resistant ovarian cancers. 3-AP (96 mg/m(2)) infusions produced modest methemoglobinemia, the expected consequence of ribonucleotide reductase inhibitors disrupting collateral proteins containing iron. TRIAL REGISTRY ClinicalTrials.gov NCT00081276.
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Heat shock protein 90 inhibitors reduce trafficking of ATP-gated P2X1 receptors and human platelet responsiveness.
Lalo, U, Jones, S, Roberts, JA, Mahaut-Smith, MP, Evans, RJ
The Journal of biological chemistry. 2012;(39):32747-54
Abstract
We have used selective inhibitors to determine whether the molecular chaperone heat shock protein 90 (HSP90) has an effect on both recombinant and native human P2X1 receptors. P2X1 receptor currents in HEK293 cells were reduced by ∼70-85% by the selective HSP90 inhibitor geldanamycin (2 μM, 20 min). This was associated with a speeding in the time course of desensitization as well as a reduction in cell surface expression. Imaging in real time of photoactivatable GFP-tagged P2X receptors showed that they are highly mobile. Geldanamycin almost abolished this movement for P2X1 receptors but had no effect on P2X2 receptor trafficking. P2X1/2 receptor chimeras showed that the intracellular N and C termini were involved in geldanamycin sensitivity. Geldanamycin also inhibited native P2X1 receptor-mediated responses. Platelet P2X1 receptors play an important role in hemostasis, contribute to amplification of signaling to a range of stimuli including collagen, and are novel targets for antithrombotic therapies. Platelet P2X1 receptor-, but not P2Y1 receptor-, mediated increases in intracellular calcium were reduced by 40-45% following HSP90 inhibition with geldanamycin or radicicol. Collagen stimulation leads to ATP release from platelets, and calcium increases to low doses of collagen were also reduced by ∼40% by the HSP90 inhibitors consistent with an effect on P2X1 receptors. These studies suggest that HSP90 inhibitors may be as effective as selective antagonists in regulating platelet P2X1 receptors, and their potential effects on hemostasis should be considered in clinical studies.
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Repeated administration of berberine inhibits cytochromes P450 in humans.
Guo, Y, Chen, Y, Tan, ZR, Klaassen, CD, Zhou, HH
European journal of clinical pharmacology. 2012;(2):213-7
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PURPOSE Berberine is a plant alkaloid that is widely used to treat gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia. Many studies have reported interactions between berberine-containing products and cytochromes P450 (CYPs), but little is known about whether berberine alters CYP activities in humans, especially after repeated doses. METHODS A two-phase randomized-crossover clinical study in healthy male subjects was performed. After 2 weeks of berberine (300 mg, t.i.d., p.o.) administration, midazolam, omeprazole, dextromethorphan, losartan, and caffeine were used to evaluate enzyme activities of CYP3A4, 2C19, 2D6, 2C9, and CYP1A2, respectively. RESULTS A decrease in CYP2D6 activity was observed as the 0-8 h urinary dextromethorphan/dextrorphan increased ninefold (P < 0.01). In addition, losartan/E-3174 ratio doubled (P < 0.01) after BBR administration, indicating a decrease in CYP2C9 activity. CYP3A4 activity was also inhibited, as the C(max), AUC(0-∞), and AUC(0-12) of midazolam were increased 38% (P < 0.05), 40% (P < 0.01), and 37% (P < 0.05) after BBR treatment, respectively. Compared with the placebo period, the T(max) and T(1/2) of midazolam during BBR administration were prolonged from 3.03 ± 0.27 to 3.66 ± 0.37 h and 0.66 ± 0.08 to 0.99 ± 0.09 h, respectively; the oral clearance of midazolam was decreased 27% (P < 0.05); and the phenotypic indices of 1 h midazolam/1'-hydroxymidazolam increased 59% (P < 0.01). There were no statistically significant differences in the pharmacokinetic parameters of the other probe drugs between placebo and the BBR-treated group. CONCLUSIONS Repeated administration of berberine (300 mg, t.i.d., p.o.) decreased CYP2D6, 2C9, and CYP3A4 activities. Drug-drug interactions should be considered when berberine is administered.