scholarly journals Steady-State Pharmacokinetic and Safety Profiles of Voriconazole and Ritonavir in Healthy Male Subjects

2007 ◽  
Vol 51 (10) ◽  
pp. 3617-3626 ◽  
Author(s):  
Ping Liu ◽  
Grover Foster ◽  
Kuan Gandelman ◽  
Robert R. LaBadie ◽  
Mark J. Allison ◽  
...  
Keyword(s):  
Steady State ◽  
Low Dose ◽  
Safety Data ◽  
Fold Increase ◽  
High Dose ◽  
Time Curve ◽  
Period 2 ◽  
Parallel Group ◽  
Male Subjects ◽  
Parallel Group Trial

ABSTRACT Since there is a likelihood of coadministration of voriconazole and ritonavir, two studies were conducted to evaluate the potential of drug interaction. Study A was a randomized, placebo-controlled, two-period, parallel-group trial (n = 34). Study B had the same design without the placebo group (n = 17). In period 1, subjects received 200 mg voriconazole or placebo twice daily (BID) for 3 days (400 mg BID on day 1). In period 2, following a 7-day washout, subjects received ritonavir alone at 400 mg BID (study A) or 100 mg BID (study B) for 10 days (days 11 to 20), and then ritonavir was coadministered with 200 mg BID voriconazole or placebo for the next 10 days (days 21 to 30). Serial plasma samples were collected on days 3, 20, and 30, and safety data were collected throughout the study. High-dose (400 mg BID) ritonavir substantially reduced the steady-state mean voriconazole exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12], −82%; maximum concentration [C max], −66%). However, the effect of low-dose (100 mg BID) ritonavir was less pronounced (AUC0-12, −39%; C max, −24%). The decrease in voriconazole exposure was probably due to the induction of CYP2C19 and CYP2C9 by ritonavir. It is interesting that one subject in each study exhibited the opposite effect of ritonavir on voriconazole exposure (a 2.5- to 3-fold increase), probably due to lack of CYP2C19. Voriconazole had no apparent effect on the exposure of high-dose ritonavir but slightly decreased the exposure of low-dose ritonavir (AUC0-12, −14%; C max, −24%). The safety profile of combination therapy was not notably different from that of voriconazole or ritonavir alone. Due to the significant effect of ritonavir on voriconazole exposure, coadministration of voriconazole with 400 mg BID ritonavir is contraindicated; coadministration with 100 mg BID ritonavir should be avoided, unless an assessment of the benefit/risk to the patient justifies the use.

scholarly journals Pharmacokinetic Interaction between Voriconazole and Methadone at Steady State in Patients on Methadone Therapy

2006 ◽  
Vol 51 (1) ◽  
pp. 110-118 ◽  
Author(s):  
Ping Liu ◽  
Grover Foster ◽  
Robert LaBadie ◽  
Eugene Somoza ◽  
Amarnath Sharma
Keyword(s):  
Steady State ◽  
Safety Data ◽  
Pharmacokinetic Interaction ◽  
Tolerability Profile ◽  
Time Curve ◽  
Parallel Group ◽  
Male Patients ◽  
The Mean ◽  
Methadone Patients ◽  
Pharmacologically Active

ABSTRACT This trial was aimed to estimate the pharmacokinetic interaction between voriconazole and methadone at steady state in male patients on methadone therapy and to characterize the safety and tolerability profile during the coadministration. Twenty-three patients on individualized methadone therapy (30 to 100 mg once daily) were enrolled into this randomized, patient- and investigator-blind, placebo-controlled, parallel-group study. Methadone pharmacokinetic samples were collected from patients receiving methadone alone as the baseline before they were randomized to coadminister either 200 mg voriconazole twice daily (BID) (400-mg BID loading doses on the first day) (n = 16) or matching placebo (n = 7) for the next 5 days. Pharmacokinetic samples for methadone and voriconazole were collected on the last day of voriconazole dosing. The safety data were collected throughout the study. Voriconazole increased the steady-state exposure of pharmacologically active enantiomer (R)-methadone: the mean area under the concentration-time curve from 0 to 24 h (AUC0-24) was increased by 47.2% (90% confidence intervals [CI]: 37.7%, 57.4%), and the mean peak concentration (C max) was increased by 30.7% (90% CI: 22.2%, 39.8%). The magnitude of increase in (S)-methadone exposure was greater than that of (R)-methadone: the AUC0-24 was increased by 103.4% (90% CI: 85.0%, 123.6%), and the C max was increased by 65.4% (90% CI: 52.6%, 79.2%). Methadone appeared to have no effect on the steady-state voriconazole pharmacokinetics compared to the historical data for voriconazole alone. Methadone patients receiving voriconazole showed no signs or symptoms of significant opioid withdrawal or overdose. Coadministration of 200 mg voriconazole BID with methadone was generally safe and well tolerated. Nevertheless, caution should be exercised when voriconazole is coadministered with methadone due to the increase in (R)-methadone exposure, which in turn may require a dose reduction of methadone.

Abstract 11532: Randomized Trial of the Association Between Low Dose Statins and Nutraceuticals in High intensity Statin. intolerRant patiENts With Very High Risk Coronary Artery disease (ADHERENCE)

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
giuseppe marazzi ◽  
francesco pelliccia ◽  
maurizio volterrani ◽  
giuseppe campolongo ◽  
salvatore rosanio ◽  
...  
Keyword(s):  
High Risk ◽  
Low Dose ◽  
Primary Objective ◽  
High Dose ◽  
Red Yeast Rice ◽  
Atherosclerotic Cardiovascular Disease ◽  
Double Blind ◽  
Parallel Group ◽  
Artery Disease ◽  
Treatment Tolerance

Background: Several trials have shown that in patients (pts) with atherosclerotic cardiovascular disease, reduction of LDL-C level with statin is associated with significant reductions in mortality and cardiovascular events. In clinical practice, however, high dose statin (HDS) treatment is often discontinued by pts due to side effects. Indeed, in statin intolerant pts alternative therapies such as nutraceuticals are available. Purpose: The primary objective of this study is to compare the efficacy and tollerability of low dose statin (LDS) therapy vs the association between a LDS and a nutraceuticals in HDS intollerant pts with CAD deemed to be at high risk. Methods: A randomised, prospective, parallel group, double blind trial was designed. The inclusion criteria were pts with CAD that underwent to PCI and that do not achieved at least a 50% reduction in LDL C and were HDS intolerant in treatment with LDS. These pts were randomized 1:1 in 2 groups: group NS received an association with LDS and a commercially available nutraceutical pill (1 tablet/day containing red yeast rice 200 mg, policosanol 10 mg and berberine 500 mg) and group S continued LDS (10 to 20 mg/day of simvastatin or 5 to 10 mg/day atorvastatin or 5 mg/day rosuvastatin). At baseline and after 3 months all pts underwent to clinical evaluation and blood exams. Results: 100 pts were consecutively enrolled. Baseline clinical features and lipid profiles were similar between groups. At the 3° month, the 2 groups significantly differed for LDL-C, total cholesterol and triglycerides, with lower levels in the NS group than in the S group; also, the 2 groups differed for HDL-C values but not significantly, with higher levels in the NS group than in the S group (Table 1). Morever, in both group the treatment tolerance was high: in each groups only 3 pts discontinued therapy. Conclusion: In pts with CAD and HDS intolerant, a treatment with LDS and Nutraceuticals can be a reliable treatment option. (clinicaltrials.gov: NCT02001883)

Pharmacokinetics, safety and tolerability of ravidasvir, with and without danoprevir/ritonavir, in healthy subjects

2021 ◽  
Author(s):  
Guolan Wu ◽  
Huili Zhou ◽  
Jing Wu ◽  
Duo Lv ◽  
Lihua Wu ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Fold Increase ◽  
Sequential Design ◽  
Maximum Plasma ◽  
Double Blind ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Multiple Doses

Ravidasvir (RDV) is a novel oral hepatitis C virus NS5A inhibitor. This study aimed to evaluate the pharmacokinetics and safety of RDV and the drug–drug interaction between RDV and ritonavir-boosted danoprevir (DNVr) in healthy adults. In 1 st study, healthy volunteers were administered oral single doses of 100, 200 and 300 mg RDV and 200 mg once daily for 7 days. The 2 nd study was randomized, double-blind and placebo-controlled sequential design (day 1 for 200 mg RDV alone, day 7 for 100 mg/100 mg DNVr, day 13 for 200 mg RDV plus 100mg/100mg DNVr, followed by RDV 200 mg once daily with DNVr 100mg/100mg twice daily for 10 days). The results showed that RDV exposure increased in a dose-proportional manner following a single dose with no evidence of accumulation with multiple doses. Co-administration with DNVr regimen (100 mg/100 mg, twice daily) resulted in a 2.92- and 1.99-fold increase in minimum plasma concentration at steady state (C min,ss ) and area under the concentration–time curve at steady state (AUC τ ) of RDV. With co-administration of RDV, maximum plasma concentration (C max ) and area under the concentration curve from zero to 12 h (AUC 0-12 ) of DNV increased 1.71-fold and 2.33-fold, respectively. We did not observe any significant changes in ritonavir exposure. Both single and multiple doses of RDV with or without DNVr were well tolerated. The favorable pharmacokinetic and safety results support ravidasvir’s continued clinical development and treatment.

scholarly journals Safety of Short-Term Supplementation with Methylliberine (Dynamine®) Alone and in Combination with TeaCrine® in Young Adults

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 654 ◽  
Author(s):  
Trisha A. VanDusseldorp ◽  
Matthew T. Stratton ◽  
Alyssa R. Bailly ◽  
Alyssa J. Holmes ◽  
Michaela G. Alesi ◽  
...  
Keyword(s):  
Low Dose ◽  
Safety Data ◽  
High Density Lipoproteins ◽  
High Dose ◽  
Mean Corpuscular Hemoglobin ◽  
Blood Biomarkers ◽  
Purine Alkaloids ◽  
Clinically Significant ◽  
Continuous Use ◽  
Main Effects

Methylliberine (Dynamine®; DYM) and theacrine (Teacrine®; TCR) are purine alkaloids purported to have similar neuro-energetic effects as caffeine. There are no published human safety data on DYM, and research on TCR is limited. The purpose of this study was to examine the effect of four weeks of DYM supplementation with and without TCR on cardiovascular function and blood biomarkers. One-hundred twenty-five men and women (mean age 23.0 yrs, height 169.7 cm, body mass 72.1 kg; n = 25/group) were randomly assigned to one of five groups: low-dose DYM (100 mg), high-dose DYM (150 mg), low-dose DYM with TCR (100 mg + 50 mg), high-dose DYM with TCR (150 mg + 25 mg), and placebo. Regardless of group and sex, significant main effects for time were noted for heart rate, systolic blood pressure, and QTc (p < 0.001), high-density lipoproteins (p = 0.002), mean corpuscular hemoglobin (p = 0.018), basophils (p = 0.006), absolute eosinophils (p = 0.010), creatinine (p = 0.004), estimated glomerular filtration rate (p = 0.037), chloride (p = 0.030), carbon dioxide (p = 0.023), bilirubin (p = 0.027), and alanine aminotransferase (p = 0.043), among others. While small changes were found in some cardiovascular and blood biomarkers, no clinically significant changes occurred. This suggests that DYM alone or in combination with TCR consumed at the dosages used in this study does not appear to negatively affect markers of health over four weeks of continuous use.

Neuroimmunological Effects of Exposure to Methylmercury Forms in the Sprague-Dawley Rats. Activation of the Hypothalamic-Pituitary-Adrenal Axis and Lymphocyte Responsiveness

1997 ◽  
Vol 13 (1) ◽  
pp. 57-66 ◽  
Author(s):  
Hector G. Ortega ◽  
Manuel Lopez ◽  
Atsushi Takaki ◽  
Qin-Heng Huang ◽  
Akira Arimura ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Low Dose ◽  
Fold Increase ◽  
Exposed Group ◽  
Blood Levels ◽  
High Dose ◽  
Sprague Dawley ◽  
Short Term ◽  
Hypothalamic Pituitary Adrenal ◽  
Short Term Exposure

The effects of different methylmercury (MeHg) forms on the immune system and the hypothalamic pituitary adrenal (HPA) axis were assessed. The lymphocyte response to Concanavalin A (Con A) stimulation, blood levels of interleukin-6 (IL-6), adrenocorticotrophin hormone (ACTH), and corticosterone in the presence of different MeHg compounds was measured. Rats were exposed to methylmercury sulfide [(MeHg)2S] and methylmercury chloride (MeHgCl) at concentrations of 5 and 500 μg per liter in the drinking water for 8 or 16 weeks. Short-term exposure (8 weeks) at both, low- and high-doses of (MeHg)2S significantly enhanced lymphocyte responsiveness. MeHgCl only induced increased lymphocyte responsiveness at the low-dose exposure. Circulating levels of IL-6 after short-term exposure were increased in the MeHgCl-exposed group. The HPA axis activation was demonstrated by increased levels of ACTH and corticosterone levels. This response was predominant in low-dose exposed animals. Long-term (16 weeks) exposure resulted in a reduction in lymphocyte proliferation after both low- and high-dose MeHgCl exposures. The (MeHg)2S exposure resulted in a 3-fold increase in the proliferative response. Levels of ACTH were elevated 3-fold in the (MeHg)2S-exposed group, and no increase of corticosterone was observed in the high-dose exposed group at 8 weeks, no effect of(MeHg)2S was observed at 16 weeks. The MeHgCl exposed group showed an increase in ACTH and corticosterone levels at 8 weeks; this response was not observed at 16 weeks. These data indicate that exposure to MeHg compounds enhances T-cell proliferation in most of the cases, in a dose- and time-dependent fashion. Release of IL-6 also depends on the length of exposure. Early increases in circulating ACTH at 8 weeks also suggest activation of the HPA axis. This may contribute to the production of IL-6 and surveillance of regulatory homeostatic responses against environmental agents that mimic stress-like responses.

Abstract WP96: The Efficacy and Safety of HT047 in Patients With Acute Ischemic Stroke: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase II Trial

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Sung Hyuk Heo ◽  
Bum Joon Kim ◽  
Dae-Il Chang ◽  
Hye-Yeon Choi ◽  
Young Seo Kim ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Study Groups ◽  
High Dose ◽  
Motor Score ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Parallel Group

Introduction: HT047 is an herbal mixture extract of the Scutellaria baicalensis and Pueraria lobata plants, which have been widely used to treat ischemic stroke in traditional Korean medicine. The aims of this trial are to investigate whether HT047 can improve neurological status, particularly motor function, in acute ischemic stroke patients, and to determine the safety and tolerance of HT047. Methods: In this randomized, double-blind, placebo-controlled, parallel-group, phase II trial, we enrolled patients with acute ischemic stroke within the past 14 days from 8 centers in Korea. The participating patients must have a Fugl-Meyer Assessment (FMA) motor score ≤55 with arm or leg weakness, and Korean version of the National Institutes of Health Stroke Scale (K-NIHSS) score of ≥4 and ≤15. Seventy-eight participants will be randomized in a 1:1:1 ratio and given high-dose HT047 (750 mg three times a day), low-dose HT047 (500 mg three times a day), or a placebo for 12 weeks. The primary endpoint is the change in FMA motor score between baseline and week 12. The trial is registered with ClinicalTrials.gov, NCT02828540. Results: Between Aug, 2016, and Aug, 2018, we randomly assigned 78 patients to one of the three study groups, of whom 66 patients were assessed for the primary endpoint in full analysis set. The median (min, max) changes in FMA motor score of high-dose HT047 and low-dose HT047 were 24 (0, 63) and 43 (-2, 70) (placebo group=28 [0, 63], p=0.929 and p=0.705, respectively). The prevalence of favorable outcome defined as modified Rankin scale score of 0-2 were 47.6% (p=0.919) in high-dose HT047 group and 57.1% (p=0.106) in low-dose HT047 group (31.6% in placebo group). Adverse events were similar across the three study groups. Conclusions: This study is a first-in-human trial of HT047, and there were no between-group differences on the primary and secondary endpoints.

Brief intravenous infusions of oblimersen (Genasense; Bcl-2 antisense) alone and in combination with multiple agents are highly effective in human tumor xenografts

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14061-14061
Author(s):  
B. D. Brown ◽  
G. D. Paine-Murietta ◽  
T. N. Julian ◽  
R. P. Warrell
Keyword(s):  
Low Dose ◽  
Safety Data ◽  
Human Tumor ◽  
Lymphocytic Leukemia ◽  
Antisense Oligodeoxynucleotide ◽  
High Dose ◽  
Human Tumor Xenografts ◽  
Tumor Xenografts ◽  
Intravenous Infusions ◽  
Response To Chemotherapy

14061 Background: Oblimersen (OBL; Genasense®) is a phosphorothioate-modified antisense oligodeoxynucleotide (ODN) that down-regulates Bcl-2 and may enhance the response to chemotherapy in patients with melanoma and chronic lymphocytic leukemia (CLL). Extensive safety data for Genasense and other systemically administered ODNs have been obtained using low-dose continuous intravenous infusions (CIVI). However, this method is inconvenient and unsuitable for drug combinations that employ frequent or discontinuous dosing. We have now established that OBL can be effectively administered by high-dose, short IV infusions. Methods: We tested multiple treatment schedules of OBL, alone and in combination with paclitaxel, paclitaxel albumin nanoparticles, imatinib, sorafenib, sunitinib, and erlotinib against human tumor xenografts (melanoma A375, NSCLC A549 and H460, colon HT29 and SW620) grown in C.B-17/SCID mice. Results: Periodic OBL monotherapy (high dose IV Q2–3d) yielded consistently superior antitumor efficacy when compared with low- dose daily IV injections. These results have been obtained against all tumor models evaluated to date. This increased efficacy was also observed when OBL was combined with any other therapeutic agent. For combination treatments that included taxanes, efficacy was shown to be schedule dependent. Conclusions: These results, and recent clinical observations, suggest that brief high-dose IV infusions of OBL may significantly increase antitumor activity, and may obviate the need for CIVI. Brief high-dose IV infusions are being incorporated into ongoing clinical trials to evaluate the safety and efficacy of OBL in combination with other agents. No significant financial relationships to disclose.

Pharmacokinetics of low-dose and high-dose buprenorphine in cats after rectal administration of different formulations

2018 ◽  
Vol 21 (10) ◽  
pp. 938-943
Author(s):  
Maike Schroers ◽  
Andrea Meyer-Lindenberg ◽  
Sven Reese ◽  
Britta Dobenecker ◽  
Korbinian Pieper
Keyword(s):  
Plasma Concentration ◽  
Low Dose ◽  
Ph Value ◽  
Plasma Concentrations ◽  
Rectal Administration ◽  
High Dose ◽  
Time Curve ◽  
Maximal Plasma Concentration ◽  
Wide Range ◽  
Maximal Plasma

Objectives A prospective experimental study was performed in nine young healthy cats to investigate a pharmacokinetic profile and the clinical relevance of rectally administered buprenorphine. Rectal pH value was measured in all nine cats. Methods Blood was collected 15, 30, 60, 90, 120, 240 and 480 mins and 24 h after the rectal administration of a suppository and a gel at doses between 0.02 mg/kg and 0.1 mg/kg buprenorphine to determine the plasma concentration of buprenorphine. Rectal pH was measured with pH paper. Results Upon pharmacokinetic non-compartment analysis of high-dose buprenorphine (0.1 mg/kg), average maximal plasma concentration was found to be 1.13 ng/ml, time to maximal plasma concentration was 45 mins and area under the plasma concentration–time curve was 94.19 ng*min/ml, representing low but potential bioavailability. Mean residual time was 152.2 mins and the half-life was 92.6 mins. A wide range of plasma concentrations within the cohort was measured and two of the cats had to be excluded from statistical analysis owing to incomplete uptake. Vital parameters of all cats were considered to be normal but three of the cats showed mydriasis up to 8 h after application. After the administration of a low-dose suppository or a rectal gel (0.02 mg/kg) within pilot studies, no buprenorphine was detected in cat plasma. Rectal pH in all cats was between 7.7 and 8. Conclusions and relevance The rectal application of buprenorphine at a dose of 0.1 mg/kg revealed a potential but weak uptake in cats. Regarding effective concentrations in previous pharmacokinetic investigations, rectal administration is currently not recommended for good provision of opioid analgesia in cats. Pharmacological investigations of formulation and galenics in order to improve the rectal bioavailability of buprenorphine remain to be clarified before further dose-finding and pharmacokinetic/pharmacodynamic studies are performed.

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